Linked diimidazole derivatives

ABSTRACT

The present invention discloses compounds of Formula (I), or pharmaceutically acceptable salts, esters, or prodrugs thereof: 
     
       
         
         
             
             
         
       
     
     which inhibit RNA-containing virus, particularly the hepatitis C virus (HCV). Consequently, the compounds of the present invention interfere with the life cycle of the hepatitis C virus and are also useful as antiviral agents. The present invention further relates to pharmaceutical compositions comprising the aforementioned compounds for administration to a subject suffering from HCV infection. The invention also relates to methods of treating an HCV infection in a subject by administering a pharmaceutical composition comprising the compounds of the present invention.

RELATED APPLICATION

This application claims the benefit of U.S. Provisional Application No.61/153,240, filed Feb. 17, 2009 and U.S. Provisional Application No.61/156,284 filed Feb. 27, 2009. The entire teachings of the aboveapplications are incorporated herein by reference.

TECHNICAL FIELD

The present invention relates to novel antiviral agents. Morespecifically, the present invention relates to compounds which caninhibit the function of the NS5A protein encoded by Hepatitis C virus(HCV), compositions comprising such compounds, methods for inhibitingHCV viral replication, and methods for treating or preventing HCVinfection.

BACKGROUND OF THE INVENTION

Infection with HCV is a major cause of human liver disease throughoutthe world. In the US, an estimated 4.5 million Americans are chronicallyinfected with HCV. Although only 30% of acute infections aresymptomatic, greater than 85% of infected individuals develop chronic,persistent infection. Treatment costs for HCV infection have beenestimated at $5.46 billion for the US in 1997. Worldwide over 200million people are estimated to be infected chronically. HCV infectionis responsible for 40-60% of all chronic liver disease and 30% of allliver transplants. Chronic HCV infection accounts for 30% of allcirrhosis, end-stage liver disease, and liver cancer in the U.S. The CDCestimates that the number of deaths due to HCV will minimally increaseto 38,000/year by the year 2010.

Due to the high degree of variability in the viral surface antigens,existence of multiple viral genotypes, and demonstrated specificity ofimmunity, the development of a successful vaccine in the near future isunlikely. Alpha-interferon (alone or in combination with ribavirin) hasbeen widely used since its approval for treatment of chronic HCVinfection. However, adverse side effects are commonly associated withthis treatment: flu-like symptoms, leukopenia, thrombocytopenia,depression from interferon, as well as anemia induced by ribavirin(Lindsay, K. L. (1997) Hepatology 26 (suppl 1): 71S-77S). This therapyremains less effective against infections caused by HCV genotype 1(which constitutes ˜75% of all HCV infections in the developed markets)compared to infections caused by the other 5 major HCV genotypes.Unfortunately, only ˜50-80% of the patients respond to this treatment(measured by a reduction in serum HCV RNA levels and normalization ofliver enzymes) and, of responders, 50-70% relapse within 6 months ofcessation of treatment. Recently, with the introduction of pegylatedinterferon (Peg-IFN), both initial and sustained response rates haveimproved substantially, and combination treatment of Peg-IFN withribavirin constitutes the gold standard for therapy. However, the sideeffects associated with combination therapy and the impaired response inpatients with genotype 1 present opportunities for improvement in themanagement of this disease.

First identified by molecular cloning in 1989 (Choo, Q-L et al (1989)Science 244:359-362), HCV is now widely accepted as the most commoncausative agent of post-transfusion non-A, non-B hepatitis (NANBH) (Kuo,G et al (1989) Science 244:362-364). Due to its genome structure andsequence homology, this virus was assigned as a new genus in theFlaviviridae family. Like the other members of the Flaviviridae, such asflaviviruses (e.g. yellow fever virus and Dengue virus types 1-4) andpestiviruses (e.g. bovine viral diarrhea virus, border disease virus,and classic swine fever virus) (Choo, Q-L et al (1989) Science244:359-362; Miller, R. H. and R. H. Purcell (1990) Proc. Natl. Acad.Sci. USA 87:2057-2061), HCV is an enveloped virus containing a singlestrand RNA molecule of positive polarity. The HCV genome isapproximately 9.6 kilobases (kb) with a long, highly conserved,noncapped 5′ nontranslated region (NTR) of approximately 340 bases whichfunctions as an internal ribosome entry site (IRES) (Wang C Y et al).‘An RNA pseudoknot is an essential structural element of the internalribosome entry site located within the hepatitis C virus 5′ noncodingregion’ RNA—A Publication of the RNA Society. 1(5): 526-537, 1995 July).This element is followed by a region which encodes a single long openreading frame (ORF) encoding a polypeptide of ˜3000 amino acidscomprising both the structural and nonstructural viral proteins.

Upon entry into the cytoplasm of the cell, this RNA is directlytranslated into a polypeptide of ˜3000 amino acids comprising both thestructural and nonstructural viral proteins. This large polypeptide issubsequently processed into the individual structural and nonstructuralproteins by a combination of host and virally-encoded proteinases (Rice,C. M. (1996) in B. N. Fields, D. M. Knipe and P. M. Howley (eds)Virology 2^(nd) Edition, p 931-960; Raven Press, N.Y.). There are threestructural proteins, C, E1 and E2. The P7 protein is of unknown functionand is comprised of a highly variable sequence. There are severalnon-structural proteins. NS2 is a zinc-dependent metalloproteinase thatfunctions in conjunction with a portion of the NS3 protein. NS3incorporates two catalytic functions (separate from its association withNS2): a serine protease at the N-terminal end, which requires NS4A as acofactor, and an ATP-ase-dependent helicase function at the carboxylterminus. NS4A is a tightly associated but non-covalent cofactor of theserine protease. NS5A is a membrane-anchored phosphoprotein that isobserved in basally phosphorylated (56 kDa) and hyperphosphorylated (58kDa) forms. While its function has not fully been elucidated, NS5A isbelieved to be important in viral replication. The NS5B protein (591amino acids, 65 kDa) of HCV (Behrens, S. E. et al (1996) EMBO J. 1512-22), encodes an RNA-dependent RNA polymerase (RdRp) activity andcontains canonical motifs present in other RNA viral polymerases. TheNS5B protein is fairly well conserved both intra-typically (˜95-98%amino acid (aa) identity across 1b isolates) and inter-typically (˜85%aa identity between genotype 1a and 1b isolates). The essentiality ofthe HCV NS5B RdRp activity for the generation of infectious progenyvirions has been formally proven in chimpanzees (A. A. Kolykhalov et al.(2000) Journal of Virology, 74(4): 2046-2051). Thus, inhibition of NS5BRdRp activity (inhibition of RNA replication) is predicted to be usefulto treat HCV infection.

Following the termination codon at the end of the long ORF, there is a3′ NTR which roughly consists of three regions: an ˜40 base region whichis poorly conserved among various genotypes, a variable lengthpoly(U)/polypyrimidine tract, and a highly conserved 98 base elementalso called the “3′ X-tail” (Kolykhalov, A. et al (1996) J. Virology70:3363-3371; Tanaka, T. et al (1995) Biochem Biophys. Res. Commun.215744-749; Tanaka, T. et al (1996) J. Virology 70:3307-3312; Yamada, N.et al (1996) Virology 223:255-261). The 3′NTR is predicted to form astable secondary structure which is essential for HCV growth in chimpsand is believed to function in the initiation and regulation of viralRNA replication.

Compounds useful for treating HCV-infected patients are desired whichselectively inhibit HCV viral replication. In particular, compoundswhich are effective to inhibit the function of the NS5A protein aredesired. The HCV NS5A protein is described, for example, in Tan, S.-L.,Katzel, M. G. Virology 2001, 284, 1; and in Rice, C. M. Nature 2005,435, 374.

Based on the foregoing, there exists a significant need to identifycompounds with the ability to inhibit HCV. A general strategy for thedevelopment of antiviral agents is to inactivate virally encodedproteins, including NS5A, that are essential for the replication of thevirus. The relevant patent disclosures describing the synthesis of HCVNS5A inhibitors are: US 2009/0202478; US 2009/0202483; WO 2009/020828;WO 2009/020825; WO 2009/102318; WO 2009/102325; WO 2009/102694; WO2008/144380; WO 2008/021927; WO 2008/021928; WO 2008/021936; WO2006/1333262; WO 2004/014852; WO 2008/070447; WO 2009/034390; WO2006/079833; WO 2007/031791; WO 2007/070556; WO 2007/070600; WO2008/064218; WO 2008/154601; WO 2007/082554 and WO 2008/048589, thecontents of each of which are expressly incorporated by referenceherein.

SUMMARY OF THE INVENTION

The present invention relates to novel antiviral compounds representedherein below, pharmaceutical compositions comprising such compounds, andmethods for the treatment or prophylaxis of viral (particularly HCV)infection in a subject in need of such therapy with said compounds.Compounds of the present invention interfere with the life cycle of thehepatitis C virus and are also useful as antiviral agents.

In its principal aspect, the present invention provides a compound ofFormula (I)

or a pharmaceutically acceptable salt thereof, wherein:

A is absent or a cyclic group independently selected from aryl,heteroaryl, heterocyclic, C₃-C₈ cycloalkyl, and C₃-C₈ cycloalkenyl, eachoptionally substituted;

Y is absent or an optionally substituted aliphatic group selected fromthe group consisting of O, S, N(R¹¹), C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈alkynyl, C₃-C₈ cycloalkyl, C₃-C₈ cycloalkenyl, and heterocyclic, eachoptionally substituted; or a combination thereof;

Z is absent or an optionally substituted linear aliphatic group;optionally Z contains a group selected from O, N(R¹¹), C(O), S(O)₂,C(O)O, C(O)N(R¹¹), OC(O)O, OC(O)N(R¹¹), S(O)₂N(R¹¹), N(R¹¹)C(O)N(R¹¹),N(R¹¹)C(O)C(O)N(R¹¹), N(R¹¹)S(O)₂N(R¹¹), C(O)N(R¹¹)S(O)₂ andC(O)N(R¹¹)S(O)₂N(R¹¹);

Wherein at least two of A, Y, and Z are present;

R¹¹ at each occurrence is independently hydrogen or optionallysubstituted C₁-C₈ alkyl;

R¹ and R² at each occurrence are each independently selected from thegroup consisting of hydrogen, halogen, cyano, optionally substitutedC₁-C₄ alkyl, —O—R¹¹, —NR^(a)R^(b), —C(O)R¹¹, —CO₂R¹¹, and—C(O)NR^(a)R^(b); preferably hydrogen, halogen and optionallysubstituted C₁-C₄ alkyl;

R^(a) and R^(b) at each occurrence are each independently selected fromthe group consisting of hydrogen, optionally substituted C₁-C₈ alkyl,and optionally substituted C₂-C₈ alkenyl; or R^(a) and R^(b) can betaken together with the nitrogen atom to which they are attached to forman optionally substituted heterocyclic or optionally substitutedheteroaryl group;

Q and J are each independently selected from:

R³ and R⁴ at each occurrence are each independently selected from thegroup consisting of hydrogen, optionally substituted C₁-C₈ alkyl,optionally substituted C₂-C₈ alkenyl, and optionally substituted C₃-C₈cycloalkyl; preferably hydrogen or optionally substituted C₁-C₄ alkyl;or alternatively, R³ and R⁴ can be taken together with the carbon atomto which they are attached to form optionally substituted C₃-C₈cycloalkyl or optionally substituted heterocyclic;

R⁵ at each occurrence is independently hydrogen, optionally substitutedC₁-C₈ alkyl, or optionally substituted C₃-C₈ cycloalkyl; preferablyhydrogen or optionally substituted C₁-C₄ alkyl;

R⁶ at each occurrence is independently selected from the groupconsisting of —C(O)—R¹², —C(O)—C(O)—R¹², —S(O)₂—R¹², and —C(S)—R¹²,preferably —C(O)—R¹², more preferably an optionally substituted aminoacid acyl;

R¹² at each occurrence is independently selected from the groupconsisting of: —O—R¹¹, —NR^(a)R^(b), —R¹³, and —NR^(c)R^(d), preferablyoptionally substituted C₁-C₈ alkyl and —O—R¹¹;

R¹³ at each occurrence is independently selected from the groupconsisting of hydrogen, C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, C₃-C₈cycloalkyl, C₃-C₈ cycloalkenyl, heterocyclic, aryl, and heteroaryl, eachoptionally substituted; preferably optionally substituted C₁-C₈ alkyl;more preferably C₁-C₈ alkyl optionally substituted with amino, hydroxy,optionally substituted phenyl, protected amino, or O(C₁-C₄ alkyl); and

R^(c) and R^(d) at each occurrence are each independently selected fromthe group consisting of hydrogen, —R¹³, —C(O)—R¹³, —C(O)—OR¹³,—S(O)₂—R¹³, —C(O)N(R¹³)₂, and —S(O)₂N(R¹³)₂;

m is 0, 1, or 2, preferably 1;

n is 1, 2, 3, or 4, preferably 1 or 2;

X at each occurrence is independently selected from O, S, S(O), SO₂, andC(R⁷)₂, preferably CH₂ or CHR⁷; provided that when m is 0, X is C(R⁷)₂;and

R⁷ at each occurrence is independently selected from the groupconsisting of hydrogen, halogen, cyano, —O—R¹¹, —NR^(a)R^(b), optionallysubstituted aryl, optionally substituted heteroaryl, and optionallysubstituted —C₁-C₄ alkyl; preferably hydrogen, methyl or halogen; or twovicinal R⁷ groups can be taken together with the two adjacent atoms towhich they are attached to form a fused, optionally substituted C₃-C₈cycloalkyl or optionally substituted heterocyclic ring; preferably afused, optionally substituted cyclopropyl; or alternatively two geminalR⁷ groups can be taken together with the carbon atom to which they areattached to form a spiro, optionally substituted C₃-C₈ cycloalkyl oroptionally substituted heterocyclic ring; preferably a spiro, optionallysubstituted cyclopropyl.

Each preferred group stated above can be taken in combination with one,any or all other preferred groups.

In another aspect, the present invention provides a pharmaceuticalcomposition comprising a therapeutically effective amount of a compoundor combination of compounds of the present invention, or apharmaceutically acceptable salt form, prodrug, salt of a prodrug,stereoisomer, tautomer, solvate, or combination thereof, in combinationwith a pharmaceutically acceptable carrier or excipient.

In yet another aspect, the present invention provides a method ofinhibiting the replication of a RNA-containing virus comprisingcontacting said virus with a therapeutically effective amount of acompound or a combination of compounds of the present invention, or apharmaceutically acceptable salt, prodrug, salt of a prodrug,stereoisomer, tautomer, solvate, or combination thereof. Particularly,this invention is directed to methods of inhibiting the replication ofHCV.

In still another aspect, the present invention provides a method oftreating or preventing infection caused by an RNA-containing viruscomprising administering to a patient in need of such treatment atherapeutically effective amount of a compound or combination ofcompounds of the present invention, or a pharmaceutically acceptablesalt form, prodrug, salt of a prodrug, stereoisomer, or tautomer,solvate, or combination thereof. Particularly, this invention isdirected to methods of treating or preventing infection caused by HCV.

Yet another aspect of the present invention provides the use of acompound or combination of compounds of the present invention, or atherapeutically acceptable salt form, prodrug, salt of a prodrug,stereoisomer or tautomer, solvate, or combination thereof, as definedhereinafter, in the preparation of a medicament for the treatment orprevention of infection caused by RNA-containing virus, specificallyHCV.

DETAILED DESCRIPTION OF THE INVENTION

In an embodiment of the present invention is a compound of Formula (I)as illustrated above, or a pharmaceutically acceptable salt, ester orprodrug thereof.

The compounds of the invention have utility in inhibiting thereplication of RNA-containing virus, including, for example, HCV. Othercompounds useful for inhibiting the replication of RNA-containingviruses and/or for the treatment or prophylaxis of HCV infection havebeen described in copending U.S. application Ser. No. 12/702,673entitled “Linked Dibenzimidazole Antivirals”; U.S. application Ser. No.12/702,692 entitled “Linked Dibenzimidazole Derivatives”; U.S.application Ser. No. 12/702,802 entitled “Linked DibenzimidazoleDerivatives”; U.S. Provisional Application Ser. No. 61/153,234 filedFeb. 17, 2009 entitled “Linked Diimidazole Antivirals”; U.S. ProvisionalApplication Ser. No. 61/156,160 filed Feb. 27, 2009 entitled “LinkedDiimidazole Antivirals”; and U.S. Provisional Application Ser. No.61/156,268 filed Feb. 27, 2009 entitled “Hepatitis C Virus Inhibitors”;the contents of each of which are expressly incorporated by referenceherein.

In another embodiment of the present invention relates to compounds ofFormula (Ia), or a pharmaceutically acceptable salt thereof:

wherein A, Y, Z, R¹, R², R³, R⁴, R⁵ and R⁶ are as previously defined.

In yet another embodiment of the present invention relates to compoundsof Formula (Ib), or a pharmaceutically acceptable salt thereof:

wherein A, Y, Z, m, n, R¹, R², R³, R⁴, R⁵, R⁶ and R⁷ are as previouslydefined.

In still another embodiment of the present invention relates tocompounds of Formula (Ic), or a pharmaceutically acceptable saltthereof:

wherein A, Y, Z, m, n, R¹, R², R⁶ and R⁷ are as previously defined.

In still another embodiment of the present invention relates tocompounds of Formula (Id), or a pharmaceutically acceptable saltthereof:

wherein A, Y, Z, R³, R⁴, R⁵ and R¹² are as previously defined.

In still another embodiment of the present invention relates tocompounds of Formula (Ie), or a pharmaceutically acceptable saltthereof:

wherein A, Y, Z, R³, R⁴, R⁵ and R¹² are as previously defined and X¹ ateach occurrence is independently CH₂, CHF, CH(OH), or CF₂.

In still another embodiment of the present invention relates tocompounds of Formula (If), or a pharmaceutically acceptable saltthereof:

wherein A, Y, Z, X¹ and R¹² are as previously defined.

In still another embodiment, the present invention relates to compoundsof Formula (If), wherein R¹² is C₁-C₈ alkyl optionally substituted withamino, hydroxy, phenyl, protected amino, or O(C₁-C₄ alkyl); or apharmaceutically acceptable salt thereof.

In still another embodiment of the present invention is the absolutestereochemistry of the pyrrolidine and 2-imidazolylmethylamine moiety,is represented by Formulae (Ig-1, Ig-2 and Ig-3):

wherein A, Y, Z, R³, R⁵, and R¹² are as previously defined.

In still another embodiment, the present invention relates to compoundsof Formula (Ih), or a pharmaceutically acceptable salt thereof:

wherein A, Y, Z, X¹ and R¹¹ are as previously defined.

In still another embodiment, the present invention relates to compoundsof Formula (Ii), or a pharmaceutically acceptable salt thereof:

wherein A, Y, Z, X¹, R^(a) and R^(b) are as previously defined.

In still another embodiment, the present invention relates to compoundsof Formula (Ij), or a pharmaceutically acceptable salt thereof:

wherein A, Y, Z, X¹, R^(c) and R^(d) are as previously defined.

In still another embodiment, the present invention relates to compoundsof Formula (Ik), or a pharmaceutically acceptable salt thereof:

wherein A, Y, Z, X¹ and R¹³ are as previously defined.

In still another embodiment, the present invention relates to compoundsof Formula (Il), or a pharmaceutically acceptable salt thereof:

wherein A, Y, Z and X¹ are as previously defined and R^(13a) at eachoccurrence is independently an optionally substituted C₁-C₈ alkyl;preferably C₁-C₈ alkyl optionally substituted with amino, hydroxy,phenyl, protected amino, or O(C₁-C₄ alkyl).

In still another embodiment of the present invention relates tocompounds of Formula (IIa), or a pharmaceutically acceptable saltthereof:

wherein Q, J, R¹ and R² are as previously defined; Y and Z are eachpresent and as previously defined.

In still another embodiment of the present invention relates tocompounds of Formula (IIb), or a pharmaceutically acceptable saltthereof:

wherein Q, J, R¹ and R² are as previously defined; A and Y are eachpresent and as previously defined.

In still another embodiment of the present invention relates tocompounds of Formula (IIc), or a pharmaceutically acceptable saltthereof:

wherein Q, J, R¹ and R² are as previously defined; A and Z are eachpresent and as previously defined.

In still another embodiment of the present invention relates tocompounds of Formula (IId), or a pharmaceutically acceptable saltthereof:

wherein Q, J, R¹ and R² are as previously defined; A, Y and Z are eachpresent and as previously defined.

In still another embodiment of the present invention relates tocompounds of Formula (IIIa), or a pharmaceutically acceptable saltthereof:

wherein Q, J, R¹ and R² are as previously defined; Z is present and aspreviously defined; and Y¹ is independently C₁-C₈ alkyl, C₂-C₈ alkenyl,or C₂-C₈ alkynyl, each optionally substituted.

In still another embodiment of the present invention relates tocompounds of Formula (IIIb), or a pharmaceutically acceptable saltthereof:

wherein Q, J, R¹ and R² are as previously defined; Y is present and aspreviously defined; and Z¹ is independently C₁-C₈ alkyl, C₂-C₈ alkenyl,or C₂-C₈ alkynyl, or Z¹ is a group containing between one and eightcarbon atoms and optionally contains one group independently selectedfrom O, N(R¹¹), C(O), S(O)₂, C(O)O, C(O)N(R¹¹), OC(O)O, OC(O)N(R¹¹),S(O)₂N(R¹¹), N(R¹¹)C(O)N(R¹¹), N(R¹¹)C(O)C(O)N(R¹¹), N(R¹¹)S(O)₂N(R¹¹),C(O)N(R¹¹)S(O)₂ and C(O)N(R¹¹)S(O)₂N(R¹¹); and R¹¹ is as previouslydefined.

In still another embodiment of the present invention relates tocompounds of Formula (IIIc), or a pharmaceutically acceptable saltthereof:

wherein Q, J, Z¹, R¹ and R² are as previously defined and Y² is anoptionally substituted C₃-C₈ cycloalkyl or optionally substituted C₃-C₈cycloalkenyl.

In still another embodiment of the present invention relates tocompounds of Formula (IIId), or a pharmaceutically acceptable saltthereof:

wherein Q, J, Z¹, R¹ and R² are as previously defined and Y³ is anoptionally substituted heterocyclic.

In still another embodiment of the present invention relates tocompounds of Formula (IIIe), or a pharmaceutically acceptable saltthereof:

wherein Q, J, R¹ and R² are as previously defined; Y is present and aspreviously defined; and A¹ is an optionally substituted aryl.

In still another embodiment of the present invention relates tocompounds of Formula (IIIf), or a pharmaceutically acceptable saltthereof:

wherein Q, J, R¹ and R² are as previously defined; Y is present and aspreviously defined; and A² is an optionally substituted heteroaryl.

In still another embodiment of the present invention relates tocompounds of Formula (IIIg), or a pharmaceutically acceptable saltthereof:

wherein Q, J, R¹ and R² are as previously defined; Y is present and aspreviously defined; and A³ is an optionally substituted heterocyclic.

In still another embodiment of the present invention relates tocompounds of Formula (IIIh), or a pharmaceutically acceptable saltthereof:

wherein Q, J, R¹ and R² are as previously defined; Y is present and aspreviously defined; and A⁴ is an optionally substituted C₃-C₈cycloalkyl.

In still another embodiment of the present invention relates tocompounds of Formula (IIIi), or a pharmaceutically acceptable saltthereof:

wherein Q, J, R¹ and R² are as previously defined; Y is present and aspreviously defined; and A⁵ is an optionally substituted C₃-C₈cycloalkenyl.

In still another embodiment of the present invention relates tocompounds of Formula (IIIj), or a pharmaceutically acceptable saltthereof:

wherein Q, J, R¹ and R² are as previously defined; A and Z¹ are eachpresent and as previously defined.

In still another embodiment of the present invention relates tocompounds of Formula (IIIk), or a pharmaceutically acceptable saltthereof:

wherein Q, J, Z¹, R¹ and R² are as previously defined; A and Y are eachpresent and as previously defined.

In still another embodiment of the present invention relates tocompounds of Formula (IVa), or a pharmaceutically acceptable saltthereof:

wherein Q, J, R¹ and R² are as previously defined; and u and v at eachoccurrence are each independently 0, 1, 2, or 3, preferably 0 or 1.

In still another embodiment of the present invention relates tocompounds of Formula (IVb), or a pharmaceutically acceptable saltthereof:

wherein Q, J, u, v, R¹ and R² are as previously defined.

In still another embodiment of the present invention relates tocompounds of Formula (IVc), or a pharmaceutically acceptable saltthereof:

wherein Q, J, u, v, R¹ and R² are as previously defined.

In still another embodiment of the present invention relates tocompounds of Formula (IVd), or a pharmaceutically acceptable saltthereof:

wherein Q, J, u and R¹ are as previously defined.

In still another embodiment, the present invention relates to compoundsof Formula (I), or a pharmaceutically acceptable salt thereof; wherein

at each occurrence is independently illustrated by one of the followinggroups:

Representative compounds of the present invention are those selectedfrom compounds 1-a˜1-d (shown below) and compounds 1-368 compiled in thefollowing tables:

TABLE 1 Compounds 1-219

Entry

Entry

Entry

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

32

33

34

35

36

37

38

39

40

41

42

43

44

45

46

47

48

49

50

51

52

53

54

55

56

57

58

59

60

61

62

63

64

65

66

67

68

69

70

71

72

73

74

75

76

77

78

79

80

81

82

83

84

85

86

87

88

89

90

91

92

93

94

95

96

97

98

99

100

101

102

103

104

105

106

107

108

109

110

111

112

113

114

115

116

117

118

119

120

121

122

123

124

125

126

127

128

129

130

131

132

133

134

135

136

137

138

139

140

141

142

143

144

145

146

147

148

149

150

151

152

153

154

155

156

157

158

159

160

161

162

163

164

165

166

167

168

169

170

171

172

173

174

175

176

177

178

179

180

181

182

183

184

185

186

187

188

189

190

191

192

193

194

195

196

197

198

199

200

201

202

203

204

205

206

207

208

209

210

211

212

213

214

215

216

217

218

219

TABLE 2 Compounds 220-229

Entry R R′ R″ X Entry R R′ R″ X 220 Me H H CH₂ 221 H H H CF₂ 222 Me H HS 223 H H H

224 Me H H O 225 H H H

226 H Ph H CH₂ 227 H H H

228 H H Ph CH₂ 229 H H H

TABLE 3 Compounds 234-243

Entry R R′ R″ Entry R R′ R″ 234 Me Me H 235 H Me H 236 Me H Me 237cyclopropyl Me H 238 Me Me Me 239 Me cyclopropyl H 240 Me Allyl H 241 EtMe H 242 Me CHMe₂ H 243 Me Et H.

TABLE 4 Compounds 244-263

Entry R R′ 244

245

246

247

248

249

250

251

252

253

254

255

256

257

258

259

260

261

262

263

TABLE 5 Compounds 264-283

Entry R R′ R″ R′′′ Entry R R′ R″ R′′′ 264 F H H H 265 F H F H 266 F F HH 267 Me H H H 268 Me Me H H 269 Me H Me H 270 CF₃ H H H 271 CF₃ H CF₃ H272 CF₃ CF₃ H H 273 CO₂Me H H H 274 CONH₂ H H H 275 CO₂H H H H 276 CH₂OHH H H 277 CH₂NMe₂ H H H 278 NMe₂ H H H 279 OMe H H H 280 OCF₃ H H H 281NHCO₂Me H H H 282 Cl H H H 283 Cl H Cl H.

TABLE 6 Compounds 284-360

Entry A^(a) Entry A^(a) 284

285

286

287

288

289

290

291

292

293

294

295

296

297

298

299

300

301

302

303

304

305

306

307

310

311

312

313

314

315

316

317

318

319

320

321

322

323

324

325

326

327

328

329

330

331

332

333

334

335

336

337

338

339

340

341

342

343

344

345

346

347

348

349

350

351

352

353

354

355

356

357

358

359

360

TABLE 7 Compounds 361-368 361

362

363

364

365

366

367

368

It will be appreciated that the description of the present inventionherein should be construed in congruity with the laws and principals ofchemical bonding. In some instances it may be necessary to remove ahydrogen atom in order to accommodate a substitutent at any givenlocation.

It is intended that the definition of any substituent or variable (e.g.,R¹, R², m, etc.) at a particular location in a molecule be independentof its definitions elsewhere in that molecule. For example, when u is 2,each of the two R¹ groups may be the same or different.

It will be yet appreciated that the compounds of the present inventionmay contain one or more asymmetric carbon atoms and may exist inracemic, diastereoisomeric, and optically active forms. It will still beappreciated that certain compounds of the present invention may exist indifferent tautomeric forms. All tautomers are contemplated to be withinthe scope of the present invention.

It should be understood that the compounds encompassed by the presentinvention are those that are suitably stable for use as pharmaceuticalagent.

It will be further appreciated that reference herein to therapy and/ortreatment includes, but is not limited to, prevention, retardation,prophylaxis, therapy and cure of the disease. It will further beappreciated that references herein to treatment or prophylaxis of HCVinfection includes treatment or prophylaxis of HCV-associated diseasesuch as liver fibrosis, cirrhosis and hepatocellular carcinoma.

A further embodiment of the present invention includes pharmaceuticalcompositions comprising any single compound or a combination of two ormore compounds delineated herein, or a pharmaceutically acceptable saltthereof, with a pharmaceutically acceptable carrier or excipient.

Yet a further embodiment of the present invention is a pharmaceuticalcomposition comprising any single compound or a combination of two ormore compounds delineated herein, or a pharmaceutically acceptable saltthereof, in combination with one or more agents known in the art, with apharmaceutically acceptable carrier or excipient.

It will be further appreciated that compounds of the present inventioncan be administered as the sole active pharmaceutical agent, or used incombination with one or more agents to treat or prevent hepatitis Cinfections or the symptoms associated with HCV infection. Other agentsto be administered in combination with a compound or combination ofcompounds of the present invention include therapies for disease causedby HCV infection that suppresses HCV viral replication by direct orindirect mechanisms. These agents include, but not limited to, hostimmune modulators (for example, interferon-alpha, pegylatedinterferon-alpha, consensus interferon, interferon-beta,interferon-gamma, CpG oligonucleotides and the like); antiviralcompounds that inhibit host cellular functions such as inosinemonophosphate dehydrogenase (for example, ribavirin and the like);cytokines that modulate immune function (for example, interleukin 2,interleukin 6, and interleukin 12); a compound that enhances thedevelopment of type 1 helper T cell response; interfering RNA;anti-sense RNA; vaccines comprising HCV antigens or antigen adjuvantcombinations directed against HCV; agents that interact with hostcellular components to block viral protein synthesis by inhibiting theinternal ribosome entry site (IRES) initiated translation step of HCVviral replication or to block viral particle maturation and release withagents targeted toward the viroporin family of membrane proteins suchas, for example, HCV P7 and the like; and any agent or combination ofagents that inhibit the replication of HCV by targeting other proteinsof the viral genome involved in the viral replication and/or interferewith the function of other viral targets, such as inhibitors of NS3/NS4Aprotease, NS3 helicase, NS5B polymerase, NS4A protein and NS5A protein.

According to yet another embodiment, the pharmaceutical compositions ofthe present invention may further comprise other inhibitor(s) of targetsin the HCV life cycle, including, but not limited to, helicase,polymerase, metalloprotease, NS4A protein, NS5A protein, and internalribosome entry site (IRES).

Accordingly, one embodiment of the present invention is directed to amethod for treating or preventing an infection caused by anRNA-containing virus comprising co-administering to a patient in need ofsuch treatment one or more agents selected from the group consisting ofa host immune modulator and a second or more antiviral agents, or acombination thereof, with a therapeutically effective amount of acompound or combination of compounds of the present invention, or apharmaceutically acceptable salt thereof.

Examples of the host immune modulator are, but not limited to,interferon-alpha, pegylated-interferon-alpha, interferon-beta,interferon-gamma, a cytokine, a vaccine, and a vaccine comprising anantigen and an adjuvant, and said second antiviral agent inhibitsreplication of HCV either by inhibiting host cellular functionsassociated with viral replication or by targeting proteins of the viralgenome. A non-limiting example of the RNA-containing virus is hepatitisC virus (HCV).

A further embodiment of the present invention is directed to a method oftreating or preventing infection caused by an RNA-containing viruscomprising co-administering to a patient in need of such treatment anagent or combination of agents that treat or alleviate symptoms of HCVinfection including cirrhosis and inflammation of the liver, with atherapeutically effective amount of a compound or combination ofcompounds of the present invention, or a pharmaceutically acceptablesalt thereof. A non-limiting example of the RNA-containing virus ishepatitis C virus (HCV).

Yet another embodiment of the present invention provides a method oftreating or preventing infection caused by an RNA-containing viruscomprising co-administering to a patient in need of such treatment oneor more agents that treat patients for disease caused by hepatitis B(HBV) infection, with a therapeutically effective amount of a compoundor a combination of compounds of the present invention, or apharmaceutically acceptable salt thereof. An agent that treats patientsfor disease caused by hepatitis B (HBV) infection may be for example,but not limited thereto, L-deoxythymidine, adefovir, lamivudine ortenfovir, or any combination thereof. A non-limiting example of theRNA-containing virus is hepatitis C virus (HCV).

Another further embodiment of the present invention provides a method oftreating or preventing infection caused by an RNA-containing viruscomprising co-administering to a patient in need of such treatment oneor more agents that treat patients for disease caused by humanimmunodeficiency virus (HIV) infection, with a therapeutically effectiveamount of a compound or a combination of compounds of the presentinvention, or a pharmaceutically acceptable salt thereof. The agent thattreats patients for disease caused by human immunodeficiency virus (HIV)infection may include, but is not limited thereto, ritonavir, lopinavir,indinavir, nelfinavir, saquinavir, amprenavir, atazanavir, tipranavir,TMC-114, fosamprenavir, zidovudine, lamivudine, didanosine, stavudine,tenofovir, zalcitabine, abacavir, efavirenz, nevirapine, delavirdine,TMC-125, L-870812, S-1360, enfuvirtide (T-20) or T-1249, or anycombination thereof. A non-limiting example of the RNA-containing virusis hepatitis C virus (HCV).

It can occur that a patient may be co-infected with hepatitis C virusand one or more other viruses, including but not limited to humanimmunodeficiency virus (HIV), hepatitis A virus (HAV) and hepatitis Bvirus (HBV). Thus also contemplated herein is combination therapy totreat such co-infections by co-administering a compound according to thepresent invention with at least one of an HIV inhibitor, an HAVinhibitor and an HBV inhibitor.

In addition, the present invention provides the use of a compound or acombination of compounds of the invention, or a therapeuticallyacceptable salt thereof, and one or more agents selected from the groupconsisting of a host immune modulator and one or more additionalantiviral agents, or a combination thereof, to prepare a medicament forthe treatment of an infection caused by an RNA-containing virus in apatient, particularly hepatitis C virus. Examples of the host immunemodulator are, but not limited to, interferon-alpha,pegylated-interferon-alpha, interferon-beta, interferon-gamma, acytokine, a vaccine, and a vaccine comprising an antigen and anadjuvant. Preferably said additional antiviral agent inhibitsreplication of HCV either by inhibiting host cellular functionsassociated with viral replication or by targeting proteins of the viralgenome.

When used in the above or other treatments, combination of compound orcompounds of the present invention, together with one or more agents asdefined herein above, can be employed in pure form or, where such formsexist, or as a pharmaceutically acceptable salt thereof. Alternatively,such combination of therapeutic agents can be administered as apharmaceutical composition containing a therapeutically effective amountof the compound or combination of compounds of interest, or theirpharmaceutically acceptable salt thereof, in combination with one ormore agents as defined hereinabove, and a pharmaceutically acceptablecarrier. Such pharmaceutical compositions can be used for inhibiting thereplication of an RNA-containing virus, particularly Hepatitis C virus(HCV), by contacting said virus with said pharmaceutical composition. Inaddition, such compositions are useful for the treatment or preventionof an infection caused by an RNA-containing virus, particularlyHepatitis C virus (HCV).

Hence, a still further embodiment of the invention is directed to amethod of treating or preventing infection caused by an RNA-containingvirus, particularly a hepatitis C virus (HCV), comprising administeringto a patient in need of such treatment a pharmaceutical compositioncomprising a compound or combination of compounds of the invention or apharmaceutically acceptable salt thereof, and one or more agents asdefined hereinabove, with a pharmaceutically acceptable carrier.

When administered as a combination, the therapeutic agents can beformulated as separate compositions which are given at the same time orwithin a predetermined period of time, or the therapeutic agents can begiven as a single unit dosage form.

Antiviral agents contemplated for use in such combination therapyinclude agents (compounds or biologicals) that are effective to inhibitthe formation and/or replication of a virus in a mammal, including butnot limited to agents that interfere with either host or viralmechanisms necessary for the formation and/or replication of a virus ina mammal. Such agents can be selected from another anti-HCV agent; anHIV inhibitor; an HAV inhibitor; and an HBV inhibitor.

Other agents that can be administered in combination with a compound ofthe present invention include a cytochrome P450 monooxygenase inhibitor(also referred to herein as a CYP inhibitor), which is expected toinhibit metabolism of the compounds of the invention. Therefore, thecytochrome P450 monooxygenase inhibitor would be in an amount effectiveto inhibit metabolism of the compounds of this invention. Accordingly,the CYP inhibitor is administered in an amount sufficient to increasethe bioavailiablity of a compound of the invention when thebioavailability is increased in comparison to the bioavailability in theabsence of the CYP inhibitor.

In one embodiment, the invention provides methods for improving thepharmacokinetics of compounds of the invention. The advantages ofimproving the pharmacokinetics of drugs are recognized in the art (see,for example, US Patent App. Nos. 2004/0091527; US 2004/0152625; and US2004/0091527). Accordingly, one embodiment of this invention provides amethod comprising administering an inhibitor of CYP3A4 and a compound ofthe invention. Another embodiment of this invention provides a methodcomprising administering a compound of the invention and an inhibitor ofisozyme 3A4 (“CYP3A4”), isozyme 2C19 (“CYP2C19”), isozyme 2D6(“CYP2D6”), isozyme 1A2 (“CYP1A2”), isozyme 2C9 (“CYP2C9”), or isozyme2E1 (“CYP2E1”). In a preferred embodiment, the CYP inhibitor preferablyinhibits CYP3A4. Any CYP inhibitor that improves the pharmacokinetics ofthe relevant compound of the invention may be used in a method of thisinvention. These CYP inhibitors include, but are not limited to,ritonavir (see, for example, WO 94/14436), ketoconazole, troleandomycin,4-methylpyrazole, cyclosporin, clomethiazole, cimetidine, itraconazole,fluconazole, miconazole, fluvoxamine, fluoxetine, nefazodone,sertraline, indinavir, nelfinavir, amprenavir, fosamprenavir,saquinavir, lopinavir, delavirdine, erythromycin, VX-944, and VX-497.Preferred CYP inhibitors include ritonavir, ketoconazole,troleandomycin, 4-methylpyrazole, cyclosporin, and clomethiazole.

It will be understood that the administration of the combination of theinvention by means of a single patient pack, or patient packs of eachformulation, containing within a package insert instructing the patientto the correct use of the invention is a desirable additional feature ofthis invention.

According to a further aspect of the invention is a pack comprising atleast a compound of the invention and a CYP inhibitor and an informationinsert containing directions on the use of the combination of theinvention. In an alternative embodiment of this invention, the packfurther comprises one or more of additional agent as described herein.The additional agent or agents may be provided in the same pack or inseparate packs.

Another aspect of this involves a packaged kit for a patient to use inthe treatment of HCV infection or in the prevention of HCV infection,comprising: a single or a plurality of pharmaceutical formulation ofeach pharmaceutical component; a container housing the pharmaceuticalformulation (s) during storage and prior to administration; andinstructions for carrying out drug administration in a manner effectiveto treat or prevent HCV infection.

Accordingly, this invention provides kits for the simultaneous orsequential administration of a compound of the invention and a CYPinhibitor (and optionally an additional agent) or derivatives thereofare prepared in a conventional manner. Typically, such a kit willcomprise, e.g. a composition of a compound of the invention andoptionally the additional agent (s) in a pharmaceutically acceptablecarrier (and in one or in a plurality of pharmaceutical formulations)and written instructions for the simultaneous or sequentialadministration.

In another embodiment, a packaged kit is provided that contains one ormore dosage forms for self administration; a container means, preferablysealed, for housing the dosage forms during storage and prior to use;and instructions for a patient to carry out drug administration. Theinstructions will typically be written instructions on a package insert,a label, and/or on other components of the kit, and the dosage form orforms are as described herein. Each dosage form may be individuallyhoused, as in a sheet of a metal foil-plastic laminate with each dosageform isolated from the others in individual cells or bubbles, or thedosage forms may be housed in a single container, as in a plasticbottle. The present kits will also typically include means for packagingthe individual kit components, i.e., the dosage forms, the containermeans, and the written instructions for use. Such packaging means maytake the form of a cardboard or paper box, a plastic or foil pouch, etc.

DEFINITIONS

Listed below are definitions of various terms used to describe thisinvention. These definitions apply to the terms as they are usedthroughout this specification and claims, unless otherwise limited inspecific instances, either individually or as part of a larger group.

The term “aryl,” as used herein, refers to a mono- or polycycliccarbocyclic ring system comprising at least one aromatic ring,including, but not limited to, phenyl, naphthyl, tetrahydronaphthyl,indanyl and idenyl.

The term “heteroaryl,” as used herein, refers to a mono- or polycyclicaromatic radical having one or more ring atom selected from S, O and N;and the remaining ring atoms are carbon, wherein any N or S containedwithin the ring may be optionally oxidized. Heteroaryl includes, but isnot limited to, pyridinyl, pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl,imidazolyl, thiazolyl, oxazolyl, isooxazolyl, thiadiazolyl, oxadiazolyl,thiophenyl, furanyl, quinolinyl, isoquinolinyl, benzimidazolyl,benzooxazolyl, quinoxalinyl.

In accordance with the invention, aromatic groups can be substituted orunsubstituted.

The terms “C₁-C₄ alkyl,” “C₁-C₆ alkyl,” “C₁-C₈ alkyl,” “C₂-C₄ alkyl,” or“C₂-C₆ alkyl,” as used herein, refer to saturated, straight- orbranched-chain hydrocarbon radicals containing between one and four, oneand six, one and eight carbon atoms, or the like, respectively. Examplesof C₁-C₈ alkyl radicals include, but are not limited to, methyl, ethyl,propyl, isopropyl, n-butyl, tent-butyl, neopentyl, n-hexyl, heptyl andoctyl radicals.

The terms “C₂-C₈ alkenyl,” “C₂-C₄ alkenyl,” “C₃-C₄ alkenyl,” or “C₃-C₆alkenyl,” as used herein, refer to straight- or branched-chainhydrocarbon radicals containing from two to eight, or two to four carbonatoms, or the like, having at least one carbon-carbon double bond by theremoval of a single hydrogen atom. Alkenyl groups include, but are notlimited to, for example, ethenyl, propenyl, butenyl,1-methyl-2-buten-1-yl, heptenyl, octenyl, and the like.

The terms “C₂-C₈ alkynyl,” “C₂-C₄ alkynyl,” “C₃-C₄ alkynyl,” or “C₃-C₆alkynyl,” as used herein, refer to straight- or branched-chainhydrocarbon radicals containing from two to eight, or two to four carbonatoms, or the like, having at least one carbon-carbon triple bond by theremoval of a single hydrogen atom. Representative alkynyl groupsinclude, but are not limited to, for example, ethynyl, 1-propynyl,1-butynyl, heptynyl, octynyl, and the like.

The term “C₃-C₈-cycloalkyl”, or “C₅-C₇-cycloalkyl,” as used herein,refers to a monocyclic or polycyclic saturated carbocyclic ringcompound, and the carbon atoms may be optionally oxo-substituted.Examples of C₃-C₈-cycloalkyl include, but not limited to, cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cyclopentyl and cyclooctyl; andexamples of C₅-C₇-cycloalkyl include, but not limited to, cyclopentyl,cyclohexyl, bicyclo[2.2.1]heptyl, and the like.

The term “C₃-C₈ cycloalkenyl”, or “C₅-C₇ cycloalkenyl” as used herein,refers to monocyclic or polycyclic carbocyclic ring compound having atleast one carbon-carbon double bond, and the carbon atoms may beoptionally oxo-substituted. Examples of C₃-C₈ cycloalkenyl include, butnot limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl,cyclohexenyl, cycloheptenyl, cyclooctenyl, and the like; and examples ofC₅-C₇ cycloalkenyl include, but not limited to, cyclopentenyl,cyclohexenyl, cycloheptenyl, and the like. The term “arylalkyl”, as usedherein, refers to an aryl-substituted alkyl group. More preferredarylalkyl groups are aryl-C₁-C₆-alkyl groups.

The term “heteroarylalkyl”, as used herein, refers to aheteroaryl-substituted alkyl group. More preferred heteroarylalkylgroups are heteroaryl-C₁-C₆-alkyl groups. It is understood that anyalkyl, alkenyl, alkynyl, cycloalkyl and cycloalkenyl moiety describedherein can also be an aliphatic group or an alicyclic group.

An “aliphatic” group is a non-aromatic moiety comprised of anycombination of carbon atoms, hydrogen atoms, halogen atoms, oxygen,nitrogen or other atoms, and optionally contains one or more units ofunsaturation, e.g., double and/or triple bonds. Examples of aliphaticgroups are functional groups, such as, O, OH, NH, NH₂, C(O), S(O)₂,C(O)O, C(O)NH, OC(O)O, OC(O)NH, OC(O)NH₂, S(O)₂NH, S(O)₂NH₂, NHC(O)NH₂,NHC(O)C(O)NH, NHS(O)₂NH, NHS(O)₂NH₂, C(O)NHS(O)₂, C(O)NHS(O)₂NH orC(O)NHS(O)₂NH₂, and the like, groups comprising one or more functionalgroups, non-aromatic hydrocarbons (optionally substituted), and groupswherein one or more carbons of a non-aromatic hydrocarbon (optionallysubstituted) is replaced by a functional group. Carbon atoms of analiphatic group can be optionally oxo-substituted. An aliphatic groupmay be straight chained, branched or cyclic and preferably containsbetween about 1 and about 24 carbon atoms, more typically between about1 and about 12 carbon atoms. In addition to aliphatic hydrocarbongroups, as used herein, aliphatic groups expressly include, for example,alkoxyalkyls, polyalkoxyalkyls, such as polyalkylene glycols,polyamines, and polyimines, for example. Aliphatic groups may beoptionally substituted. A linear aliphatic group is a non-cyclicaliphatic group. It is to be understood that when an aliphatic group ora linear aliphatic group is said to “contain” or “include” or “comprise”one or more specified functional groups, the linear aliphatic group canbe selected from one or more of the specified functional groups or acombination thereof, or a group wherein one or more carbons of anon-aromatic hydrocarbon (optionally substituted) is replaced by aspecified functional group. In some examples, the linear aliphatic groupcan be represented by the formula M-V-M′, where M and M′ are eachindependently absent or an alkyl, alkenyl or alkynyl, each optionallysubstituted, and V is a functional group. In some examples, V isselected from the group consisting of C(O), S(O)₂, C(O)O, C(O)N(R¹¹),OC(O)O, OC(O)N(R¹¹), S(O)₂N(R¹¹), N(R¹¹)C(O)N(R¹¹),N(R¹¹)C(O)C(O)N(R¹¹), N(R¹¹)S(O)₂N(R¹¹), C(O)N(R¹¹)S(O)₂ orC(O)N(R¹¹)S(O)₂N(R¹¹); wherein R¹¹ is as previously defined. In anotheraspect of the invention, an exemplary linear aliphatic group is analkyl, alkenyl or alkynyl, each optionally substituted, which isinterrupted or terminated by a functional group such as describedherein.

The term “alicyclic,” as used herein, denotes a monovalent group derivedfrom a monocyclic or bicyclic saturated carbocyclic ring compound by theremoval of a single hydrogen atom, and the carbon atoms may beoptionally oxo-substituted. Examples include, but not limited to,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[2.2.1]heptyl,and bicyclo[2.2.2]octyl. Such alicyclic groups may be furthersubstituted.

The terms “heterocyclic” or “heterocycloalkyl” can be usedinterchangeably and referred to a non-aromatic ring or a bi- ortri-cyclic group fused system, where (i) each ring system contains atleast one heteroatom independently selected from oxygen, sulfur andnitrogen, (ii) each ring system can be saturated or unsaturated (iii)the nitrogen and sulfur heteroatoms may optionally be oxidized, (iv) thenitrogen heteroatom may optionally be quaternized, (v) any of the aboverings may be fused to an aromatic ring, and (vi) the remaining ringatoms are carbon atoms which may be optionally oxo-substituted.Representative heterocycloalkyl groups include, but are not limited to,1,3-dioxolane, pyrrolidinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl,imidazolidinyl, piperidinyl, piperazinyl, oxazolidinyl, isoxazolidinyl,morpholinyl, thiazolidinyl, isothiazolidinyl, quinoxalinyl,pyridazinonyl, and tetrahydrofuryl. Such heterocyclic groups may befurther substituted.

It is understood that any alkyl, alkenyl, alkynyl, alicyclic,cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclic, and aliphaticmoiety, or the like, described herein can also be a divalent group whenused as a linkage to connect two groups or substituents, which can be atthe same or different atom(s).

The term “substituted” refers to substitution by independent replacementof one, two, or three or more of the hydrogen atoms with substituentsincluding, but not limited to, —F, —Cl, —Br, —I, —OH, protected hydroxy,—NO₂, —N₃, —CN, —NH₂, protected amino, oxo, thioxo, —NH—C₁-C₁₂-alkyl,—NH—C₂-C₈-alkenyl, —NH—C₂-C₈-alkynyl, —NH—C₃-C₁₂-cycloalkyl, —NH-aryl,—NH-heteroaryl, —NH-heterocycloalkyl, -dialkylamino, -diarylamino,-diheteroarylamino, —O—C₁-C₁₂-alkyl, —O—C₂-C₈-alkenyl, —O—C₂-C₈-alkynyl,—O—C₃-C₁₂-cycloalkyl, —O-aryl, —O-heteroaryl, —O-heterocycloalkyl,—C(O)—C₁-C₁₂-alkyl, —C(O)—C₂-C₈-alkenyl, —C(O)—C₂-C₈-alkynyl,—C(O)—C₃-C₁₂-cycloalkyl, —C(O)-aryl, —C(O)-heteroaryl,—C(O)-heterocycloalkyl, —CONH₂, —CONH—C₁-C₁₂-alkyl, —CONH—C₂-C₈-alkenyl,—CONH—C₂-C₈-alkynyl, —CONH—C₃-C₁₂-cycloalkyl, —CONH-aryl,—CONH-heteroaryl, —CONH-heterocycloalkyl, —OCO₂—C₁-C₁₂-alkyl,—OCO₂—C₂-C₈-alkenyl, —OCO₂—C₂-C₈-alkynyl, —OCO₂—C₃-C₁₂-cycloalkyl,—OCO₂-aryl, —OCO₂-heteroaryl, —OCO₂-heterocycloalkyl, —OCO₂—C₁-C₁₂alkyl, —OCO₂—C₂-C₈ alkenyl, —CO₂—C₂-C₈ alkynyl, CO₂—C₃-C₁₂-cycloalkyl,—CO₂— aryl, CO₂-heteroaryl, CO₂-heterocyloalkyl, —OCONH₂,—OCONH—C₁-C₁₂-alkyl, —OCONH—C₂-C₈-alkenyl, —OCONH—C₂-C₈-alkynyl,—OCONH—C₃-C₁₂-cycloalkyl, —OCONH-aryl, —OCONH-heteroaryl,—OCONH-heterocycloalkyl, —NHC(O)H, —NHC(O)—C₁-C₁₂-alkyl,—NHC(O)—C₂-C₈-alkenyl, —NHC(O)—C₂-C₈-alkynyl, —NHC(O)—C₃-C₁₂-cycloalkyl,—NHC(O)-aryl, —NHC(O)-heteroaryl, —NHC(O)-heterocycloalkyl,—NHCO₂—C₁-C₁₂-alkyl, —NHCO₂—C₂-C₈-alkenyl, —NHCO₂—C₂-C₈-alkynyl,—NHCO₂—C₃-C₁₂-cycloalkyl, —NHCO₂-aryl, —NHCO₂-heteroaryl,—NHCO₂-heterocycloalkyl, —NHC(O)NH₂, —NHC(O)NH—C₁-C₁₂-alkyl,—NHC(O)NH—C₂-C₈-alkenyl, —NHC(O)NH—C₂-C₈-alkynyl,—NHC(O)NH—C₃-C₁₂-cycloalkyl, —NHC(O)NH-aryl, —NHC(O)NH-heteroaryl,—NHC(O)NH-heterocycloalkyl, NHC(S)NH₂, —NHC(S)NH—C₁-C₁₂-alkyl,—NHC(S)NH—C₂-C₈-alkenyl, —NHC(S)NH—C₂-C₈-alkynyl,—NHC(S)NH—C₃-C₁₂-cycloalkyl, —NHC(S)NH-aryl, —NHC(S)NH-heteroaryl,—NHC(S)NH-heterocycloalkyl, —NHC(NH)NH₂, —NHC(NH)NH—C₁-C₁₂-alkyl,—NHC(NH)NH—C₂-C₈-alkenyl, —NHC(NH)NH—C₂-C₈-alkynyl,—NHC(NH)NH—C₃-C₁₂-cycloalkyl, —NHC(NH)NH-aryl, —NHC(NH)NH-heteroaryl,—NHC(NH)NH-heterocycloalkyl, —NHC(NH)—C₁-C₁₂-alkyl,—NHC(NH)—C₂-C₈-alkenyl, —NHC(NH)—C₂-C₈-alkynyl,—NHC(NH)—C₃-C₁₂-cycloalkyl, —NHC(NH)-aryl, —NHC(NH)-heteroaryl,—NHC(NH)-heterocycloalkyl, —C(NH)NH—C₁-C₁₂-alkyl,—C(NH)NH—C₂-C₈-alkenyl, —C(NH)NH—C₂-C₈-alkynyl,—C(NH)NH—C₃-C₁₂-cycloalkyl, —C(NH)NH-aryl, —C(NH)NH-heteroaryl,—C(NH)NH-heterocycloalkyl, —S(O)—C₁-C₁₂-alkyl, —S(O)—C₂-C₈-alkenyl,—S(O)—C₂-C₈-alkynyl, —S(O)—C₃-C₁₂-cycloalkyl, —S(O)-aryl,—S(O)-heteroaryl, —S(O)-heterocycloalkyl, —SO₂NH₂, —SO₂NH—C₁-C₁₂-alkyl,—SO₂NH—C₂-C₈-alkenyl, —SO₂NH—C₂-C₈-alkynyl, —SO₂NH—C₃-C₁₂-cycloalkyl,—SO₂NH-aryl, —SO₂NH-heteroaryl, —SO₂NH— heterocycloalkyl,—NHSO₂—C₁-C₁₂-alkyl, —NHSO₂—C₂-C₈-alkenyl, —NHSO₂—C₂-C₈-alkynyl,—NHSO₂—C₃-C₁₂-cycloalkyl, —NHSO₂-aryl, —NHSO₂-heteroaryl,—NHSO₂-heterocycloalkyl, —CH₂NH₂, —CH₂SO₂CH₃, -aryl, -arylalkyl,-heteroaryl, -heteroarylalkyl, -heterocycloalkyl, —C₃-C₁₂-cycloalkyl,polyalkoxyalkyl, polyalkoxy, -methoxymethoxy, -methoxyethoxy, —SH,—S—C₁-C₁₂-alkyl, —S—C₂-C₈-alkenyl, —S—C₂-C₈-alkynyl,—S—C₃-C₁₂-cycloalkyl, —S-aryl, —S-heteroaryl, —S-heterocycloalkyl, ormethylthiomethyl. It is understood that the aryls, heteroaryls, alkyls,and the like can be further substituted.

The term “halogen,” as used herein, refers to an atom selected fromfluorine, chlorine, bromine and iodine.

The term “hydrogen” includes hydrogen and deuterium. In addition, therecitation of an atom includes other isotopes of that atom so long asthe resulting compound is pharmaceutically acceptable.

The term “hydroxy activating group”, as used herein, refers to a labilechemical moiety which is known in the art to activate a hydroxyl groupso that it will depart during synthetic procedures such as in asubstitution or an elimination reaction. Examples of hydroxyl activatinggroup include, but not limited to, mesylate, tosylate, triflate,p-nitrobenzoate, phosphonate and the like.

The term “activated hydroxy”, as used herein, refers to a hydroxy groupactivated with a hydroxyl activating group, as defined above, includingmesylate, tosylate, triflate, p-nitrobenzoate, phosphonate groups, forexample.

The term “hydroxy protecting group,” as used herein, refers to a labilechemical moiety which is known in the art to protect a hydroxyl groupagainst undesired reactions during synthetic procedures. After saidsynthetic procedure(s) the hydroxy protecting group as described hereinmay be selectively removed. Hydroxy protecting groups as known in theart are described generally in T. H. Greene and P. G. M. Wuts,Protective Groups in Organic Synthesis, 3rd edition, John Wiley & Sons,New York (1999). Examples of hydroxyl protecting groups includebenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, tert-butoxycarbonyl,isopropoxycarbonyl, diphenylmethoxycarbonyl,2,2,2-trichloroethoxycarbonyl, allyloxycarbonyl, acetyl, formyl,chloroacetyl, trifluoroacetyl, methoxyacetyl, phenoxyacetyl, benzoyl,methyl, t-butyl, 2,2,2-trichloroethyl, 2-trimethylsilyl ethyl, allyl,benzyl, triphenylmethyl (trityl), methoxymethyl, methylthiomethyl,benzyloxymethyl, 2-(trimethylsilyl)ethoxymethyl, methanesulfonyl,trimethylsilyl, triisopropylsilyl, and the like.

The term “protected hydroxy,” as used herein, refers to a hydroxy groupprotected with a hydroxy protecting group, as defined above, includingbenzoyl, acetyl, trimethylsilyl, triethylsilyl, methoxymethyl groups,for example.

The term “hydroxy prodrug group”, as used herein, refers to a promoietygroup which is known in the art to change the physicochemical, and hencethe biological properties of a parent drug in a transient manner bycovering or masking the hydroxy group. After said syntheticprocedure(s), the hydroxy prodrug group as described herein must becapable of reverting back to hydroxy group in vivo. Hydroxy prodruggroups as known in the art are described generally in Kenneth B. Sloan,Prodrugs, Topical and Ocular Drug Delivery, (Drugs and thePharmaceutical Sciences; Volume 53), Marcel Dekker, Inc., New York(1992).

The term “amino protecting group,” as used herein, refers to a labilechemical moiety which is known in the art to protect an amino groupagainst undesired reactions during synthetic procedures. After saidsynthetic procedure(s) the amino protecting group as described hereinmay be selectively removed. Amino protecting groups as known in the artare described generally in T. H. Greene and P. G. M. Wuts, ProtectiveGroups in Organic Synthesis, 3rd edition, John Wiley & Sons, New York(1999). Examples of amino protecting groups include, but are not limitedto, methoxycarbonyl, t-butoxycarbonyl, 9-fluorenylmethoxycarbonyl,benzyloxycarbonyl, and the like.

The term “protected amino,” as used herein, refers to an amino groupprotected with an amino protecting group as defined above.

The term “leaving group” means a functional group or atom which can bedisplaced by another functional group or atom in a substitutionreaction, such as a nucleophilic substitution reaction. By way ofexample, representative leaving groups include chloro, bromo and iodogroups; sulfonic ester groups, such as mesylate, tosylate, brosylate,nosylate and the like; and acyloxy groups, such as acetoxy,trifluoroacetoxy and the like.

The term “aprotic solvent,” as used herein, refers to a solvent that isrelatively inert to proton activity, i.e., not acting as a proton-donor.Examples include, but are not limited to, hydrocarbons, such as hexaneand toluene, for example, halogenated hydrocarbons, such as, forexample, methylene chloride, ethylene chloride, chloroform, and thelike, heterocyclic compounds, such as, for example, tetrahydrofuran andN-methylpyrrolidinone, and ethers such as diethyl ether,bis-methoxymethyl ether. Such compounds are well known to those skilledin the art, and it will be obvious to those skilled in the art thatindividual solvents or mixtures thereof may be preferred for specificcompounds and reaction conditions, depending upon such factors as thesolubility of reagents, reactivity of reagents and preferred temperatureranges, for example. Further discussions of aprotic solvents may befound in organic chemistry textbooks or in specialized monographs, forexample: Organic Solvents Physical Properties and Methods ofPurification, 4th ed., edited by John A. Riddick et al., Vol. II, in theTechniques of Chemistry Series, John Wiley & Sons, NY, 1986.

The term “protic solvent' as used herein, refers to a solvent that tendsto provide protons, such as an alcohol, for example, methanol, ethanol,propanol, isopropanol, butanol, t-butanol, and the like. Such solventsare well known to those skilled in the art, and it will be obvious tothose skilled in the art that individual solvents or mixtures thereofmay be preferred for specific compounds and reaction conditions,depending upon such factors as the solubility of reagents, reactivity ofreagents and preferred temperature ranges, for example. Furtherdiscussions of protogenic solvents may be found in organic chemistrytextbooks or in specialized monographs, for example: Organic SolventsPhysical Properties and Methods of Purification, 4th ed., edited by JohnA. Riddick et al., Vol. II, in the Techniques of Chemistry Series, JohnWiley & Sons, NY, 1986.

Combinations of substituents and variables envisioned by this inventionare only those that result in the formation of stable compounds. Theterm “stable”, as used herein, refers to compounds which possessstability sufficient to allow manufacture and which maintains theintegrity of the compound for a sufficient period of time to be usefulfor the purposes detailed herein (e.g., therapeutic or prophylacticadministration to a subject).

The synthesized compounds can be separated from a reaction mixture andfurther purified by a method such as column chromatography, highpressure liquid chromatography, or recrystallization. As can beappreciated by the skilled artisan, further methods of synthesizing thecompounds of the Formula herein will be evident to those of ordinaryskill in the art. Additionally, the various synthetic steps may beperformed in an alternate sequence or order to give the desiredcompounds. Synthetic chemistry transformations and protecting groupmethodologies (protection and deprotection) useful in synthesizing thecompounds described herein are known in the art and include, forexample, those such as described in R. Larock, Comprehensive OrganicTransformations, 2^(nd) Ed. Wiley-VCH (1999); T. W. Greene and P. G. M.Wuts, Protective Groups in Organic Synthesis, 3rd Ed., John Wiley andSons (1999); L. Fieser and M. Fieser, Fieser and Fieser's Reagents forOrganic Synthesis, John Wiley and Sons (1994); and L. Paquette, ed.,Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons(1995), and subsequent editions thereof.

The term “subject” as used herein refers to an animal. Preferably, theanimal is a mammal. More preferably, the mammal is a human. A subjectalso refers to, for example, dogs, cats, horses, cows, pigs, guineapigs, fish, birds and the like.

The compounds of this invention may be modified by appending appropriatefunctionalities to enhance selective biological properties. Suchmodifications are known in the art and may include those which increasebiological penetration into a given biological system (e.g., blood,lymphatic system, central nervous system), increase oral availability,increase solubility to allow administration by injection, altermetabolism and alter rate of excretion.

The compounds described herein contain one or more asymmetric centersand thus give rise to enantiomers, diastereomers, and otherstereoisomeric forms that may be defined, in terms of absolutestereochemistry, as (R)— or (S)—, or as (D)—or (L)— for amino acids. Thepresent invention is meant to include all such possible isomers, as wellas their racemic and optically pure forms. Optical isomers may beprepared from their respective optically active precursors by theprocedures described above, or by resolving the racemic mixtures. Theresolution can be carried out in the presence of a resolving agent, bychromatography or by repeated crystallization or by some combination ofthese techniques which are known to those skilled in the art. Furtherdetails regarding resolutions can be found in Jacques, et al.,Enantiomers, Racemates, and Resolutions (John Wiley & Sons, 1981). Whenthe compounds described herein contain olefinic double bonds, otherunsaturation, or other centers of geometric asymmetry, and unlessspecified otherwise, it is intended that the compounds include both Eand Z geometric isomers or cis- and trans-isomers. Likewise, alltautomeric forms are also intended to be included. Tautomers may be incyclic or acyclic. The configuration of any carbon-carbon double bondappearing herein is selected for convenience only and is not intended todesignate a particular configuration unless the text so states; thus acarbon-carbon double bond or carbon-heteroatom double bond depictedarbitrarily herein as trans may be cis, trans, or a mixture of the twoin any proportion.

Certain compounds of the present invention may also exist in differentstable conformational forms which may be separable. Torsional asymmetrydue to restricted rotation about an asymmetric single bond, for examplebecause of steric hindrance or ring strain, may permit separation ofdifferent conformers. The present invention includes each conformationalisomer of these compounds and mixtures thereof.

As used herein, the term “pharmaceutically acceptable salt” refers tothose salts which are, within the scope of sound medical judgment,suitable for use in contact with the tissues of humans and lower animalswithout undue toxicity, irritation, allergic response and the like, andare commensurate with a reasonable benefit/risk ratio. Pharmaceuticallyacceptable salts are well known in the art. For example, S. M. Berge, etal. describes pharmaceutically acceptable salts in detail in J.Pharmaceutical Sciences, 66: 1-19 (1977). The salts can be prepared insitu during the final isolation and purification of the compounds of theinvention, or separately by reacting the free base function with asuitable organic acid. Examples of pharmaceutically acceptable saltsinclude, but are not limited to, nontoxic acid addition salts are saltsof an amino group formed with inorganic acids such as hydrochloric acid,hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid orwith organic acids such as acetic acid, maleic acid, tartaric acid,citric acid, succinic acid or malonic acid or by using other methodsused in the art such as ion exchange. Other pharmaceutically acceptablesalts include, but are not limited to, adipate, alginate, ascorbate,aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate,camphorate, camphorsulfonate, citrate, cyclopentanepropionate,digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate,glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate,hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate,lactate, laurate, lauryl sulfate, malate, maleate, malonate,methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate,oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate,phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate,tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts,and the like. Representative alkali or alkaline earth metal saltsinclude sodium, lithium, potassium, calcium, magnesium, and the like.Further pharmaceutically acceptable salts include, when appropriate,nontoxic ammonium, quaternary ammonium, and amine cations formed usingcounterions such as halide, hydroxide, carboxylate, sulfate, phosphate,nitrate, alkyl having from 1 to 6 carbon atoms, sulfonate and arylsulfonate.

As used herein, the term “pharmaceutically acceptable ester” refers toesters which hydrolyze in vivo and include those that break down readilyin the human body to leave the parent compound or a salt thereof.Suitable ester groups include, for example, those derived frompharmaceutically acceptable aliphatic carboxylic acids, particularlyalkanoic, alkenoic, cycloalkanoic and alkanedioic acids, in which eachalkyl or alkenyl moiety advantageously has not more than 6 carbon atoms.Examples of particular esters include, but are not limited to, formates,acetates, propionates, butyrates, acrylates and ethylsuccinates.

The term “pharmaceutically acceptable prodrugs” as used herein refers tothose prodrugs of the compounds of the present invention which are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of humans and lower animals with undue toxicity,irritation, allergic response, and the like, commensurate with areasonable benefit/risk ratio, and effective for their intended use, aswell as the zwitterionic forms, where possible, of the compounds of thepresent invention. “Prodrug”, as used herein means a compound which isconvertible in vivo by metabolic means (e.g. by hydrolysis) to acompound of the invention. Various forms of prodrugs are known in theart, for example, as discussed in Bundgaard, (ed.), Design of Prodrugs,Elsevier (1985); Widder, et al. (ed.), Methods in Enzymology, vol. 4,Academic Press (1985); Krogsgaard-Larsen, et al., (ed). “Design andApplication of Prodrugs, Textbook of Drug Design and Development,Chapter 5, 113-191 (1991); Bundgaard, et al., Journal of Drug DeliverReviews, 8:1-38 (1992); Bundgaard, J. of Pharmaceutical Sciences, 77:285et seq. (1988); Higuchi and Stella (eds.) Prodrugs as Novel DrugDelivery Systems, American Chemical Society (1975); and Bernard Testa &Joachim Mayer, “Hydrolysis In Drug And Prodrug Metabolism: Chemistry,Biochemistry And Enzymology,” John Wiley and Sons, Ltd. (2002).

The present invention also relates to solvates of the compounds ofFormula (I), for example hydrates.

This invention also encompasses pharmaceutical compositions containing,and methods of treating viral infections through administering,pharmaceutically acceptable prodrugs of compounds of the invention. Forexample, compounds of the invention having free amino, amido, hydroxy orcarboxylic groups can be converted into prodrugs. Prodrugs includecompounds wherein an amino acid residue, or a polypeptide chain of twoor more (e.g., two, three or four) amino acid residues is covalentlyjoined through an amide or ester bond to a free amino, hydroxy orcarboxylic acid group of compounds of the invention. The amino acidresidues include but are not limited to the 20 naturally occurring aminoacids commonly designated by three letter symbols and also includes4-hydroxyproline, hydroxylysine, demosine, isodemosine,3-methylhistidine, norvalin, beta-alanine, gamma-aminobutyric acid,citrulline, homocysteine, homoserine, ornithine and methionine sulfone.Additional types of prodrugs are also encompassed. For instance, freecarboxyl groups can be derivatized as amides or alkyl esters. Freehydroxy groups may be derivatized using groups including but not limitedto hemisuccinates, phosphate esters, dimethylaminoacetates, andphosphoryloxymethyloxycarbonyls, as outlined in Advanced Drug DeliveryReviews, 1996, 19, 115. Carbamate prodrugs of hydroxy and amino groupsare also included, as are carbonate prodrugs, sulfonate esters andsulfate esters of hydroxy groups. Derivatization of hydroxy groups as(acyloxy)methyl and (acyloxy)ethyl ethers wherein the acyl group may bean alkyl ester, optionally substituted with groups including but notlimited to ether, amine and carboxylic acid functionalities, or wherethe acyl group is an amino acid ester as described above, are alsoencompassed. Prodrugs of this type are described in J. Med. Chem. 1996,39, 10. Free amines can also be derivatized as amides, sulfonamides orphosphonamides. All of these prodrug moieties may incorporate groupsincluding but not limited to ether, amine and carboxylic acidfunctionalities.

Pharmaceutical Compositions

The pharmaceutical compositions of the present invention comprise atherapeutically effective amount of a compound of the present inventionformulated together with one or more pharmaceutically acceptablecarriers or excipients.

As used herein, the term “pharmaceutically acceptable carrier orexcipient” means a non-toxic, inert solid, semi-solid or liquid filler,diluent, encapsulating material or formulation auxiliary of any type.Some examples of materials which can serve as pharmaceuticallyacceptable carriers are sugars such as lactose, glucose and sucrose;starches such as corn starch and potato starch; cellulose and itsderivatives such as sodium carboxymethyl cellulose, ethyl cellulose andcellulose acetate; powdered tragacanth; malt; gelatin; talc; excipientssuch as cocoa butter and suppository waxes; oils such as peanut oil,cottonseed oil, safflower oil, sesame oil, olive oil, corn oil andsoybean oil; glycols such as propylene glycol; esters such as ethyloleate and ethyl laurate; agar; buffering agents such as magnesiumhydroxide and aluminum hydroxide; alginic acid; pyrogen-free water;isotonic saline; Ringer's solution; ethyl alcohol, and phosphate buffersolutions, as well as other non-toxic compatible lubricants such assodium lauryl sulfate and magnesium stearate, as well as coloringagents, releasing agents, coating agents, sweetening, flavoring andperfuming agents, preservatives and antioxidants can also be present inthe composition, according to the judgment of the formulator.

The pharmaceutical compositions of this invention may be administeredorally, parenterally, by inhalation spray, topically, rectally, nasally,buccally, vaginally or via an implanted reservoir, preferably by oraladministration or administration by injection. The pharmaceuticalcompositions of this invention may contain any conventional non-toxicpharmaceutically-acceptable carriers, adjuvants or vehicles. In somecases, the pH of the formulation may be adjusted with pharmaceuticallyacceptable acids, bases or buffers to enhance the stability of theformulated compound or its delivery form. The term parenteral as usedherein includes subcutaneous, intracutaneous, intravenous,intramuscular, intraarticular, intraarterial, intrasynovial,intrasternal, intrathecal, intralesional and intracranial injection orinfusion techniques.

Liquid dosage forms for oral administration include pharmaceuticallyacceptable emulsions, microemulsions, solutions, suspensions, syrups andelixirs. In addition to the active compounds, the liquid dosage formsmay contain inert diluents commonly used in the art such as, forexample, water or other solvents, solubilizing agents and emulsifierssuch as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethylacetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butyleneglycol, dimethylformamide, oils (in particular, cottonseed, groundnut,corn, germ, olive, castor, and sesame oils), glycerol,tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid estersof sorbitan, and mixtures thereof. Besides inert diluents, the oralcompositions can also include adjuvants such as wetting agents,emulsifying and suspending agents, sweetening, flavoring, and perfumingagents.

Injectable preparations, for example, sterile injectable aqueous oroleaginous suspensions, may be formulated according to the known artusing suitable dispersing or wetting agents and suspending agents. Thesterile injectable preparation may also be a sterile injectablesolution, suspension or emulsion in a nontoxic parenterally acceptablediluent or solvent, for example, as a solution in 1,3-butanediol. Amongthe acceptable vehicles and solvents that may be employed are water,Ringer's solution, U.S.P. and isotonic sodium chloride solution. Inaddition, sterile, fixed oils are conventionally employed as a solventor suspending medium. For this purpose any bland fixed oil can beemployed including synthetic mono- or diglycerides. In addition, fattyacids such as oleic acid are used in the preparation of injectables.

The injectable formulations can be sterilized, for example, byfiltration through a bacterial-retaining filter, or by incorporatingsterilizing agents in the form of sterile solid compositions which canbe dissolved or dispersed in sterile water or other sterile injectablemedium prior to use.

In order to prolong the effect of a drug, it is often desirable to slowthe absorption of the drug from subcutaneous or intramuscular injection.This may be accomplished by the use of a liquid suspension ofcrystalline or amorphous material with poor water solubility. The rateof absorption of the drug then depends upon its rate of dissolution,which, in turn, may depend upon crystal size and crystalline form.Alternatively, delayed absorption of a parenterally administered drugform is accomplished by dissolving or suspending the drug in an oilvehicle. Injectable depot forms are made by forming microencapsulematrices of the drug in biodegradable polymers such aspolylactide-polyglycolide. Depending upon the ratio of drug to polymerand the nature of the particular polymer employed, the rate of drugrelease can be controlled. Examples of other biodegradable polymersinclude poly(orthoesters) and poly(anhydrides). Depot injectableformulations are also prepared by entrapping the drug in liposomes ormicroemulsions that are compatible with body tissues.

Compositions for rectal or vaginal administration are preferablysuppositories which can be prepared by mixing the compounds of thisinvention with suitable non-irritating excipients or carriers such ascocoa butter, polyethylene glycol or a suppository wax which are solidat ambient temperature but liquid at body temperature and therefore meltin the rectum or vaginal cavity and release the active compound.

Solid dosage forms for oral administration include capsules, tablets,pills, powders, and granules. In such solid dosage forms, the activecompound is mixed with at least one inert, pharmaceutically acceptableexcipient or carrier such as sodium citrate or dicalcium phosphateand/or: a) fillers or extenders such as starches, lactose, sucrose,glucose, mannitol, and silicic acid, b) binders such as, for example,carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone,sucrose, and acacia, c) humectants such as glycerol, d) disintegratingagents such as agar-agar, calcium carbonate, potato or tapioca starch,alginic acid, certain silicates, and sodium carbonate, e) solutionretarding agents such as paraffin, f) absorption accelerators such asquaternary ammonium compounds, g) wetting agents such as, for example,cetyl alcohol and glycerol monostearate, h) absorbents such as kaolinand bentonite clay, and i) lubricants such as talc, calcium stearate,magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate,and mixtures thereof. In the case of capsules, tablets and pills, thedosage form may also comprise buffering agents.

Solid compositions of a similar type may also be employed as fillers insoft and hard-filled gelatin capsules using such excipients as lactoseor milk sugar as well as high molecular weight polyethylene glycols andthe like.

The solid dosage forms of tablets, dragees, capsules, pills, andgranules can be prepared with coatings and shells such as entericcoatings and other coatings well known in the pharmaceutical formulatingart. They may optionally contain opacifying agents and can also be of acomposition that they release the active ingredient(s) only, orpreferentially, in a certain part of the intestinal tract, optionally,in a delayed manner. Examples of embedding compositions that can be usedinclude polymeric substances and waxes.

Dosage forms for topical or transdermal administration of a compound ofthis invention include ointments, pastes, creams, lotions, gels,powders, solutions, sprays, inhalants or patches. The active componentis admixed under sterile conditions with a pharmaceutically acceptablecarrier and any needed preservatives or buffers as may be required.Ophthalmic formulation, ear drops, eye ointments, powders and solutionsare also contemplated as being within the scope of this invention.

The ointments, pastes, creams and gels may contain, in addition to anactive compound of this invention, excipients such as animal andvegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulosederivatives, polyethylene glycols, silicones, bentonites, silicic acid,talc and zinc oxide, or mixtures thereof.

Powders and sprays can contain, in addition to the compounds of thisinvention, excipients such as lactose, talc, silicic acid, aluminumhydroxide, calcium silicates and polyamide powder, or mixtures of thesesubstances. Sprays can additionally contain customary propellants suchas chlorofluorohydrocarbons.

Transdermal patches have the added advantage of providing controlleddelivery of a compound to the body. Such dosage forms can be made bydissolving or dispensing the compound in the proper medium. Absorptionenhancers can also be used to increase the flux of the compound acrossthe skin. The rate can be controlled by either providing a ratecontrolling membrane or by dispersing the compound in a polymer matrixor gel.

For pulmonary delivery, a therapeutic composition of the invention isformulated and administered to the patient in solid or liquidparticulate form by direct administration e.g., inhalation into therespiratory system. Solid or liquid particulate forms of the activecompound prepared for practicing the present invention include particlesof respirable size: that is, particles of a size sufficiently small topass through the mouth and larynx upon inhalation and into the bronchiand alveoli of the lungs. Delivery of aerosolized therapeutics,particularly aerosolized antibiotics, is known in the art (see, forexample U.S. Pat. No. 5,767,068 to VanDevanter et al., U.S. Pat. No.5,508,269 to Smith et al., and WO 98/43650 by Montgomery, all of whichare incorporated herein by reference). A discussion of pulmonarydelivery of antibiotics is also found in U.S. Pat. No. 6,014,969,incorporated herein by reference.

Antiviral Activity

An inhibitory amount or dose of the compounds of the present inventionmay range from about 0.01 mg/Kg to about 500 mg/Kg, alternatively fromabout 1 to about 50 mg/Kg. Inhibitory amounts or doses will also varydepending on route of administration, as well as the possibility ofco-usage with other agents.

According to the methods of treatment of the present invention, viralinfections, conditions are treated or prevented in a patient such as ahuman or another animal by administering to the patient atherapeutically effective amount of a compound of the invention, in suchamounts and for such time as is necessary to achieve the desired result.

By a “therapeutically effective amount” of a compound of the inventionis meant an amount of the compound which confers a therapeutic effect onthe treated subject, at a reasonable benefit/risk ratio applicable toany medical treatment. The therapeutic effect may be objective (i.e.,measurable by some test or marker) or subjective (i.e., subject gives anindication of or feels an effect). An effective amount of the compounddescribed above may range from about 0.1 mg/Kg to about 500 mg/Kg,preferably from about 1 to about 50 mg/Kg. Effective doses will alsovary depending on route of administration, as well as the possibility ofco-usage with other agents. It will be understood, however, that thetotal daily usage of the compounds and compositions of the presentinvention will be decided by the attending physician within the scope ofsound medical judgment. The specific therapeutically effective doselevel for any particular patient will depend upon a variety of factorsincluding the disorder being treated and the severity of the disorder;the activity of the specific compound employed; the specific compositionemployed; the age, body weight, general health, sex and diet of thepatient; the time of administration, route of administration, and rateof excretion of the specific compound employed; the duration of thetreatment; drugs used in combination or contemporaneously with thespecific compound employed; and like factors well known in the medicalarts.

The total daily dose of the compounds of this invention administered toa human or other animal in single or in divided doses can be in amounts,for example, from 0.01 to 50 mg/kg body weight or more usually from 0.1to 25 mg/kg body weight. Single dose compositions may contain suchamounts or submultiples thereof to make up the daily dose. In general,treatment regimens according to the present invention compriseadministration to a patient in need of such treatment from about 10 mgto about 1000 mg of the compound(s) of this invention per day in singleor multiple doses.

The compounds of the present invention described herein can, forexample, be administered by injection, intravenously, intraarterially,subdermally, intraperitoneally, intramuscularly, or subcutaneously; ororally, buccally, nasally, transmucosally, topically, in an ophthalmicpreparation, or by inhalation, with a dosage ranging from about 0.1 toabout 500 mg/kg of body weight, alternatively dosages between 1 mg and1000 mg/dose, every 4 to 120 hours, or according to the requirements ofthe particular drug. The methods herein contemplate administration of aneffective amount of compound or compound composition to achieve thedesired or stated effect. Typically, the pharmaceutical compositions ofthis invention will be administered from about 1 to about 6 times perday or alternatively, as a continuous infusion. Such administration canbe used as a chronic or acute therapy. The amount of active ingredientthat may be combined with pharmaceutically exipients or carriers toproduce a single dosage form will vary depending upon the host treatedand the particular mode of administration. A typical preparation willcontain from about 5% to about 95% active compound (w/w). Alternatively,such preparations may contain from about 20% to about 80% activecompound.

Lower or higher doses than those recited above may be required. Specificdosage and treatment regimens for any particular patient will dependupon a variety of factors, including the activity of the specificcompound employed, the age, body weight, general health status, sex,diet, time of administration, rate of excretion, drug combination, theseverity and course of the disease, condition or symptoms, the patient'sdisposition to the disease, condition or symptoms, and the judgment ofthe treating physician.

Upon improvement of a patient's condition, a maintenance dose of acompound, composition or combination of this invention may beadministered, if necessary. Subsequently, the dosage or frequency ofadministration, or both, may be reduced, as a function of the symptoms,to a level at which the improved condition is retained when the symptomshave been alleviated to the desired level. Patients may, however,require intermittent treatment on a long-term basis upon any recurrenceof disease symptoms.

When the compositions of this invention comprise a combination of acompound of the Formula described herein and one or more additionaltherapeutic or prophylactic agents, both the compound and the additionalagent should be present at dosage levels of between about 1 to 100%, andmore preferably between about 5 to 95% of the dosage normallyadministered in a monotherapy regimen. The additional agents may beadministered separately, as part of a multiple dose regimen, from thecompounds of this invention. Alternatively, those agents may be part ofa single dosage form, mixed together with the compounds of thisinvention in a single composition.

The said “additional therapeutic or prophylactic agents” includes butnot limited to, immune therapies (eg. interferon), therapeutic vaccines,antifibrotic agents, anti-inflammatory agents such as corticosteroids orNSAIDs, bronchodilators such as beta-2 adrenergic agonists and xanthines(e.g. theophylline), mucolytic agents, anti-muscarinics,anti-leukotrienes, inhibitors of cell adhesion (e.g. ICAM antagonists),anti-oxidants (eg N-acetylcysteine), cytokine agonists, cytokineantagonists, lung surfactants and/or antimicrobial and anti-viral agents(eg ribavirin and amantidine). The compositions according to theinvention may also be used in combination with gene replacement therapy.

Combination and Alternation Therapy for HCV

It has been recognized that drug-resistant variants of HCV can emergeafter prolonged treatment with an antiviral agent. Drug resistance mosttypically occurs by mutation of a gene that encodes for a protein suchas an enzyme used in viral replication, and most typically in the caseof HCV, RNA polymerase, protease, or helicase.

Recently, it has been demonstrated that the efficacy of a drug against aviral infection, such as HIV, can be prolonged, augmented, or restoredby administering the drug in combination or alternation with a second,and perhaps third, antiviral compound that induces a different mutationfrom that caused by the principal drug. Alternatively, thepharmacokinetics, biodistribution, or other parameter of the drug can bealtered by such combination or alternation therapy. In general,combination therapy is typically preferred over alternation therapybecause it induces multiple simultaneous stresses on the virus.

A compound of the present invention can also be administered incombination or alternation with antiviral agent. Exemplary antiviralagents include ribavarin, interferon, interleukin or a stabilizedprodrug of any of them. More broadly described, the compound can beadministered in combination or alternation with any of the anti-HCVdrugs listed in Table 8 below.

TABLE 8 Table of anti-Hepatitis C Compounds in Current ClinicalDevelopment Pharmaceutical Drug name Drug category Company PEGASYS Longacting interferon Roche pegylated interferon alfa-2a INFERGEN Longacting interferon InterMune interferon alfacon-1 OMNIFERON Long actinginterferon Viragen natural interferon ALBUFERON Long acting interferonHuman Genome Sciences REBIF interferon beta-la Interferon Ares-SeronoOmega Interferon Interferon BioMedicine Oral Interferon alpha OralInterferon Amarillo Biosciences Interferon gamma-lb Anti-fibroticInterMune IP-501 Anti-fibrotic InterMune Merimebodib VX-497 IMPDHinhibitor Vertex (inosine monophosphate dehydrogenase) AMANTADINE(Symmetrel) Broad Antiviral Agent Endo Labs Solvay IDN-6556 Apotosisregulation Idun Pharma. XTL-002 Monclonal Antibody XTL HCV/MF59 VaccineChiron CIVACIR Polyclonal Antibody NABI Innogenetics Therapeutic vaccineVIRAMIDINE Nucleoside Analogue ICN ZADAXIN (thymosin alfa-1)Immunomodulator Sci Clone CEPLENE (histamine) Immunomodulator Maxim VX950/LY 570310 Protease inhibitor Vertex/Eli Lilly ISIS 14803 AntisenseIsis Pharmaceutical/Elan IDN-6556 Caspase inhibitor Idun PharmaceuticalsJTK 003 Polymerase Inhibitor AKROS Pharma Tarvacin Anti-PhospholipidTherapy Peregrine HCV-796 Polymerase Inhibitor ViroPharma/Wyeth CH-6Protease inhibitor Schering ANA971 Isatoribine ANADYS ANA245 IsatoribineANADYS CPG 10101 (Actilon) Immunomodulator Coley Rituximab (Rituxam)Anti-CD2O Genetech/IDEC Monoclonal Antibody NM283 (Valopicitabine)Polymerase Inhibitor Idenix Pharmaceuticals HepX ™-C Monoclonal AntibodyXTL IC41 Therapeutic Vaccine Intercell Medusa Interferon Longer actinginterferon Flamel Technology E-1 Therapeutic Vaccine InnogeneticsMultiferon Long Acting Interferon Viragen BILN 2061 Protease inhibitorBoehringer-Ingelheim TMC435350 Protease inhibitor Tibotec/MedivirTelaprevir (VX-950) Protease inhibitor Vertex Boceprevir (SCH 503034)Protease inhibitor Schering-Plough ACH-1625 Protease inhibitor AchillionABT-450 Protease inhibitor Abbott/Enanta BI-201335 Protease inhibitorBoehringer-Ingelheim PHX-1766 Protease inhibitor Phenomix VX-500Protease inhibitor Vertex MK-7009 protease inhibitor Merck R7227(ITMN-191) protease inhibitor InterMune Narlaprevir (SCH 900518)Protease inhibitor Schering/Merch Alinia (nitazoxanide) To be determinedRomark ABT-072 Polymerase Inhibitor Abbott ABT-333 Polymerase InhibitorAbbott Filibuvir (PF-00868554) Polymerase Inhibitor Pfizer VCH-916Polymerase Inhibitor Vertex R7128 (PSI6130) Polymerase InhibitorRoche/Pharmasset IDX184 Polymerase Inhibitor Idenix R1626 Polymeraseinhibitor Roche MK-3281 Polymerase inhibitor Merck PSI-7851 Polymeraseinhibitor Pharmasset ANA598 Polymerase inhibitor Anadys PharmaceuticalsBI-207127 Polymerase inhibitor Boehringer-Ingelheim GS-9190 Polymeraseinhibitor Gilead VCH-759 Polymerase Inhibitor Vertex Clemizole NS4Binhibitor Eiger Biopharmaceuticals A-832 NS5A inhibitorArrowTherapeutics BMS-790052 NS5A inhibitor Bristol-Myers-SquibbITX-5061 Entry inhibitor iTherx GS-9450 Caspase inhibitor Gilead ANA773TLR agonist Anadys CYT107 immunomodulator Cytheris SPC3649(LNA-antimiR ™-122) microRNA Santaris Pharma Debio 025 Cyclophilininhibitor Debiopharm SCY-635 Cyclophilin inhibitor Scynexis.

Unless otherwise defined, all technical and scientific terms used hereinare accorded the meaning commonly known to one of ordinary skill in theart. All publications, patents, published patent applications, and otherreferences mentioned herein are hereby incorporated by reference intheir entirety.

Abbreviations

Abbreviations which may be used in the descriptions of the scheme andthe examples that follow are: Ac for acetyl; AcOH for acetic acid; AIBNfor azobisisobutyronitrile; BINAP for2,2′-bis(diphenylphosphino)-1,1′-binaphthyl; Boc₂O fordi-tert-butyl-dicarbonate; Boc for t-butoxycarbonyl; Bpoc for1-methyl-1-(4-biphenylyl)ethyl carbonyl; BtOH for1-hydroxybenzotriazole; Bz for benzoyl; Bn for benzyl; BocNHOH fortent-butyl N-hydroxycarbamate; t-BuOK for potassium tert-butoxide;Bu₃SnH for tributyltin hydride; BOP for(benzotriazol-1-yloxy)tris(dimethylamino)phos-phoniumHexafluorophosphate; Brine for sodium chloride solution in water; Cbzfor carbobenzyloxy; CDI for carbonyldiimidazole; CH₂Cl₂ fordichloromethane; CH₃ for methyl; CH₃CN for acetonitrile; Cs₂CO₃ forcesium carbonate; CuCl for copper (I) chloride; CuI for copper (I)iodide; dba for dibenzylidene acetone; dppb for diphenylphosphinobutane; DBU for 1,8-diazabicyclo[5.4.0]undec-7-ene; DCC forN,N′-dicyclohexylcarbodiimide; DEAD for diethylazodicarboxylate; DIADfor diisopropyl azodicarboxylate; DIBAL-H for diisobutylaluminumhydride; DIPEA or (i-Pr)₂EtN for N,N-diisopropylethyl amine; Dess-Martinperiodinane for1,1,1-tris(acetyloxy)-1,1-dihydro-1,2-benziodoxol-3-(1H)-one; DMAP for4-dimethylaminopyridine; DME for 1,2-dimethoxyethane; DMF forN,N-dimethylformamide; DMSO for dimethyl sulfoxide; DMT fordi(p-methoxyphenyl)phenylmethyl or dimethoxytrityl; DPPA fordiphenylphosphoryl azide; EDC forN-(3-dimethylaminopropyl)-N′-ethylcarbodiimide; EDC HCl forN-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride; EtOAc forethyl acetate; EtOH for ethanol; Et₂O for diethyl ether; Fmoc for9-fluorenylmethoxycarbonyl; Grubbs-1 catalyst forbenzylidene-bis(tricyclohexylphosphine)dichlororuthenium; HATU forO-(7-azabenzotriazol-1-yl)-N,N,N′,N′,-tetramethyluroniumHexafluorophosphate; HCl for hydrogen chloride; HOBT for1-hydroxybenzotriazole; K₂CO₃ for potassium carbonate; n-BuLi forn-butyl lithium; i-BuLi for i-butyl lithium; t-BuLi for t-butyl lithium;PhLi for phenyl lithium; LDA for lithium diisopropylamide; LiTMP forlithium 2,2,6,6-tetramethylpiperidinate; MeOH for methanol; Mg formagnesium; MOM for methoxymethyl; Ms for mesyl or —SO₂—CH₃; Ms₂O formethanesulfonic anhydride or mesyl-anhydride; NaBH₄ for sodiumborohydride; NaBH₃CN for sodium cyanoborohydride; NaN(TMS)₂ for sodiumbis(trimethylsilyl)amide; NaCl for sodium chloride; NaH for sodiumhydride; NaHCO₃ for sodium bicarbonate or sodium hydrogen carbonate;Na₂CO₃ sodium carbonate; NaOH for sodium hydroxide; Na₂SO₄ for sodiumsulfate; NaHSO₃ for sodium bisulfite or sodium hydrogen sulfite; Na₂S₂O₃for sodium thiosulfate; NH₂NH₂ for hydrazine; NH₄HCO₃ for ammoniumbicarbonate; NH₄Cl for ammonium chloride; NMMO for N-methylmorpholineN-oxide; NaIO₄ for sodium periodate; Ni for nickel; OH for hydroxyl;OsO₄ for osmium tetroxide; Pd for palladium; Ph for phenyl; PMB forp-methoxybenzyl; POPd for dihydrogendichlorobis(di-tert-butylphosphinito-κP)palladate(II); Pd₂(dba)₃ fortris(dibenzylidene-acetone) dipalladium (0); Pd(PPh₃)₄ fortetrakis(triphenylphosphine)palladium (0); PdCl₂(PPh₃)₂ fortrans-dichlorobis(triphenylphosphine)palladium (II); Pt for platinum; Rhfor rhodium; rt for room temperature; Ru for ruthenium; SEM for(trimethylsilyl)ethoxymethyl; TBAF for tetrabutylammonium fluoride; TBSfor tent-butyl dimethylsilyl; TEA or Et₃N for triethylamine; Teoc for2-trimethylsilylethoxy-carbonyl; TFA for trifluoroacetic acid; THF fortetrahydrofuran; TMEDA for N,N,N′,N′-tetramethylethylenediamine; TPP orPPh₃ for triphenyl-phosphine; Troc for 2,2,2-trichloroethyl carbonyl; Tsfor tosyl or —SO₂—C₆H₄—CH₃; Ts₂O for tolylsulfonic anhydride ortosyl-anhydride; TsOH for p-tolylsulfonic acid; TMS for trimethylsilyl;or TMSCl for trimethylsilyl chloride.

Synthetic Methods

The compounds and processes of the present invention will be betterunderstood in connection with the following synthetic schemes thatillustrate the methods by which the compounds of the invention may beprepared. Starting materials can be obtained from commercial sources orprepared by well-established literature methods known to those ofordinary skill in the art. It will be readily apparent to one ofordinary skill in the art that the compounds defined above can besynthesized by substitution of the appropriate reactants and agents inthe syntheses shown below. It will also be readily apparent to oneskilled in the art that the selective protection and deprotection steps,as well as the order of the steps themselves, can be carried out invarying order, depending on the nature of the variables to successfullycomplete the syntheses below. The variables are as defined above unlessotherwise noted below.

The compounds of the present invention may be prepared via severaldifferent synthetic routes, depending upon the chemotypes of titlecompounds. The most straightforward way may involve generation ofimidazole-containing building blocks followed by integration with asuitable linkage. Alternatively the title compounds of the presentinvention may be prepared by imidazole ring closure from a suitableimidazole precursor with well-installed linkage.

An example of the strategies that may be used to synthesize thedifferent types of imidazole-containing coupling partners is illustratedin Scheme 1, in which R^(s) is

Protected amino aldehyde 1-1.1 may be converted to the correspondingimidazole 1-2.1 by condensation with glyoxal in the presence of ammoniaoptionally with thermal or microwave condition. Bromination of imidazole1-2.1 with bromine source such as NBS, bromine,2,4,4,6-tetrabromo-cyclohexa-2,5-dienone, or the like, in proticsolvents such as AcOH, EtOH, iPrOH, or the like, may provide dibromide1-3.1, which may then be reduced with NaHSO₃, Na₂S₂O₃, Na₂SO₃, or thelike to afford monobromide 1-4.1. The free amino group in 1-4.1 may thenbe protected with a suitable method which are known in the art to affordBoc protected bromoimidazole 1-5.1. Coupling of bromide 1-5.1 with vinylreagent 1-5.2, in which M may be selected from boron, tin, silicon,zinc, zirconium, or copper species, via Suzuki or Stille conditionswhich are known to those skilled in the art (see reviews: A. Suzuki,Pure Applied Chem. 1991, 63, 419; A. Suzuki, Handbook of OrganopalladiumChemistry for Organic Synthesis 2002, 1, 249; A. Anastasia, et al,Handbook of Organopalladium Chemistry for Organic Synthesis 2002, 1,311; F. Bellina, et al, Synthesis 2004, 2419; M. G. Organ, et al,Synthesis 2008, 2776; A. T. Lindhardt, et al, Chem.-A European J. 2008,14, 8756; E. A. B. Kantchev, et al, Angew. Chem. Int. Ed. 2007, 46,2768; V. Farina, et al, Advances in Metal-Organic Chem. 1996, 5, 1) mayprovide alkene 1-6.1. Alkene functionality in compound 1-6.1 may then betransformed to aldehyde 1-7.1 by ozonolysis or by oxidative cleavagewith reagents such as sodium periodate, sodium chlorite, or the like, inthe presence of a catalyst such as but not limited to ruthenium(III)chloride, or osmium tetraoxide, typically in solvents such as THF,water, or the like. Alcohol 1-8.1 may then be derived from reduction ofaldehyde 1-7.1 with a reductive reagent such as but not limited toNaBH₄, lithium aluminum hydride, or diisobutylaluminum hydride. Hydroxygroup in 1-8.1 may be converted to LG, which is a leaving group such asbut not limited to mesylate, triflate, bromide or iodide, using suitablemethods which are known in the art to afford compound 1-9.1. Inaddition, aldehyde 1-1.1 could be converted to cyanide 1-10.1 bycondensation with reagent such as hydroxylamine, O-acetylhydroxylamineor the like in presence of a base such as but not limited to NaOH,DIPEA, or DBU, optionally under thermal or microwave condition. Cyanide1-10.1 may be transformed to compound 1-11.1 by reaction withbenzylthiol in solvents such as THF, Et₂O, or the like, optionally inthe presence of acid such as HCl, TFA, or the like at temperaturebetween −20° C. to 100° C., preferably at rt. Compound 1-11.1 could befurther converted to amine 1-12.1 by coupling with cyanamide in thepresence of a base such as pyridine, Et₃N, DIPEA, or the like in anaprotic solvent such as chloroform, CH₂Cl₂, or the like.

With the above imidazole building blocks in hand, installation of adesired linkage A may be executed following various synthetic routes,for example, as illustrated in Scheme 2, in which R^(s′) isindependently R^(s); A^(a1), A^(a2), A^(a3) and A^(a4) are independentlyselected from aromatic, heteroaromatic or alkenyl, provided that Mattached to an unsaturated bond. Bromide 1-4.1 may be coupledindependently with reagent 2-1.1.1, 2-2.1.1, 2-3.1.1 or 2-4.1.1 viaSuzuki or Stille conditions as previously described to afford productswith a variety of functional groups at terminal such as protected alkyne2-1.1, alkene 2-2.1, alcohol 2-3.1 or amine 2-4.1. Alkynyl group inprotected alkyne 2-1.1 may be exposed to basic conditions and thereleased alkyne may be coupled to intermediate 2-1.2.1 via Sonogashiratype conditions (see review: The Sonogashira Reaction: A BoomingMethodology in Synthetic Organic Chemistry R. Chinchilla, C. Nájera,Chem. Rev. 2007; 107, 874) to afford compound 2-1.2. Alkene 2-2.1 may bereacted with alkene 2-2.2.1 via cross-metathesis reactions (see review:R. H. Grubbs (Ed.), Handbook of Metathesis, Wiley-VCH, Weinheim, 2003)to afford alkene 2-2.2. Alcohol 2-3.1 may be coupled with reagent2-3.2.1 in the presence a base such as but not limited to NaOH, NaH,t-BuOK or DIPEA, in aprotic solvents such as CH₂Cl₂, toluenene, xylenes,or the like to afford ether 2-3.2. Amine 2-4.1 may be connected withamine 2-4.2.1 to give urea 2-4.2 by treatment with reagents such asphosgene, triphosgene or the like, in the presence of a base such as butnot limited to DBU or DIPEA, in aprotic solvents such as CH₂Cl₂, THF, orthe like.

With suitably substituted imidazole-containing coupling partners, suchas those listed in Scheme 1, the compounds of the present invention maybe prepared through various coupling strategy or a combination ofstrategies to connect two suitably substituted imidazoles with asuitable linker, such as illustrated in Scheme 2. The said strategyincludes, but not limited to, Stille coupling, Suzuki coupling,Sonogashira coupling, Heck coupling, Buchwald amidation, Buchwaldamination, amide coupling, ester bond formation, William etherification,Buchwald etherification, alkylation, pericyclic reaction with differentvariations, or the like which are known to those skilled in the art.

Alternatively the compounds of the present invention may be assembled bya strategy of imidazole ring closure from a suitably substitutedprecursor, as shown in Scheme 3. Diketone 3-1.1 may be brominated byreagents such as but not limited to bromine or hydrobromous acid insolvents such as CH₂Cl₂, AcOH or the like to afford dibromide 3-2.1,which may be coupled with acid 3-2.2 in the presence of a base such asbut not limited to NaH, DIPEA, Et₃N or NaOH in aprotic solvent such asTHF, CH₃CN, DMF, CH₂Cl₂ or the like typically, to afford diester 3-3.1.Diimidazole 3-4.1 may be formed by reaction of diester 3-3.1 with anammonia reagent such as but not limited to ammonium acetate, or ammoniumchloride in aprotic solvent such as toluene, xylenes, benzene or thelike at a temperature typically between rt to 180° C.

Core 4-1.1 may then serve as a common intermediate for furtherderivatizations to 4-2.1 in two steps: 1) mono-deprotection of thelinear or cyclic amine moiety may be accomplished, for example,treatment to hydrogenolytic conditions under Pd catalyst in the presenceof a base such as potassium carbonate to remove the Cbz protectiongroup; and 2) the released amine functionality may be acylated with ancarboxylic acid under standard acylation conditions, for example acoupling reagent such as HATU in combination with an organic base suchas DIPEA can be used in this regard; alternatively, the released aminemay be reacted with an isocyanate, carbamoyl chloride or chloroformateto provide an urea or carbamate. Various carboxylic acids includingamino acids in racemic or optical form are commercially available,and/or can be synthesized in racemic or optical form, see referencescited in reviews by D. Seebach, et al, Synthesis 2009, 1; C. Cativielaand M. D. Diaz-de-Villegas, Tetrahedron: Asymmetry 2007, 18, 569; 2000,11, 645; and 1998, 9, 3517; and experimental examples compiled in patentapplication WO 2008/021927A2 by C. Bachand, et al, from BMS, which isincorporated herein by reference. 4-2.1 may be further deprotected underhydrolytic conditions in the presence of an acid such as TFA or hydrogenchloride to remove the Boc protection group and the released aminefunctionality can be further derivatized to the title compound 4-3.1using the conditions described above.

It will be appreciated that, with appropriate manipulation andprotection of any chemical functionality, synthesis of compounds ofFormula (I) is accomplished by methods analogous to those above and tothose described in the Experimental section. Suitable protecting groupscan be found, but are not restricted to, those found in T W Greene and PG M Wuts “Protective Groups in Organic Synthesis”, 3rd Ed (1999), JWiley and Sons.

All references cited herein, whether in print, electronic, computerreadable storage media or other form, are expressly incorporated byreference in their entirety, including but not limited to, abstracts,articles, journals, publications, texts, treatises, internet web sites,databases, patents, and patent publications.

EXAMPLES

The compounds and processes of the present invention will be betterunderstood in connection with the following examples, which are intendedas an illustration only and not limiting of the scope of the invention.Various changes and modifications to the disclosed embodiments will beapparent to those skilled in the art and such changes and modificationsincluding, without limitation, those relating to the chemicalstructures, substituents, derivatives, formulations and/or methods ofthe invention may be made without departing from the spirit of theinvention and the scope of the appended claims.

Although the invention has been described with respect to variouspreferred embodiments, it is not intended to be limited thereto, butrather those skilled in the art will recognize that variations andmodifications may be made therein which are within the spirit of theinvention and the scope of the appended claims.

Example 1-a

Step 1a. Into a solution of acetyl chloride (10 g, 0.127 mol) and AlCl₃(20 g, 0.15 mol) in carbon disulfide (40 mL) was added cyclohexene (10g, 0.12 mol) at −50° C. The resulting mixture was stirred at −50° C. for40 min and the liquid was quickly decanted. The residue was addedbenzene (100 mL) and the resulting slurry was heated at 45° C. for 3hours before it was slowly added into a mixture of ice and 2 M aqueousHCl. The organic phase was washed with aqueous NaOH (1 M), dried(Na₂SO₄) and evaporated. The residue was chromatographed (silica,hexane-EtOAc) to give the desired compound (1.3 g, 8.2%) as a mixture ofcis/trans isomers. ¹H NMR (CDCl₃) 7.88 (m, 2H), 7.28 (m, 2H), 2.52 (m,1H), 2.58 (m, 3H), 1.29 (m, 1H), 2.14 (m, 3H), 1.62 to 1.75 (m, 8H).

Step 1b. Into a solution of the compounds from step 1a (145 mg, 0.59mmol) in AcOH (2 mL) was added bromine (0.05 mL). The mixture wasstirred at rt for 2 hours before all volatiles were removed by rotavap.The residue was redissolved in CH₃CN (1 mL) and added slowly into asolution of NaH (87 mg, 57% in mineral oil, 2.1 mmol) andN-Boc-L-proline (508 mg, 1.3 mml) in DMF (3 mL). The resulting mixturewas stirred at 80° C. for 1 hour before being partitioned (EtOAc—aqueousNaHCO₃). The organic phase was washed with brine, dried (Na₂SO₄) andevaporated. The residue was chromatographed (silica, hexane-EtOAc) togive the desired compound as a mixture of diastereomeric mixture (201mg, 51%). ESIMS m/z=691.38 [M+Na]⁺.

Step 1c. Into a solution of the compounds from step 1b (160 mg, 0.24mmol) in xylenes (3 mL) was added NH₄OAc (462 mg, 6 mmol). The resultingmixture was heated at 150° C. for 1 hour before being partitioned(EtOAc—aqueous NaHCO₃). The organic phase was washed with aqueousNaHCO₃, dried (Na₂SO₄) and evaporated. The residue was chromatographed(silica, hexane-EtOAc) to give the title compound (65 mg, 43%) as adiastereomeric mixture. ESIMS m/z=629.42 [M+H]⁺.

Example 1-b

Step 1d. Into a solution of the compounds from step 1c (65 mg, 0.11mmol) in CH₂Cl₂ (1 mL) was added HCl in dioxane (4 M, 5 mL). Theresulting mixture was stirred at rt for 40 minutes before all volatileswere removed by rotavap. The residue was redissolved in DMF (2 mL) andwas added DIPEA (0.32 mL, 2.3 mmol), HATU (92 mg, 0.24 mmol) and(R)-(methoxycarbonyl)amino phenyl acetic acid (prepared according to WO2008/021927, 56 mg, 0.27 mmol). The resulting mixture was stirred at rtfor 40 minutes before all volatiles was removed by N₂ flow. The residuewas chromatographed (silica, CH₂Cl₂-MeOH) to give the title compounds asa mixture of diastereomers (30 mg, 36%). ESIMS m/z=811.42 [M+H]⁺.

Example 1-c

Step 1e. Into a solution of the compounds from step 1d (15 mg) in EtOH(5 mL) was added palladium (10% on carbon, 5 mg). The resulting mixturewas charged with hydrogen (60 psi) and stirred at rt for 20 hour. Theresulting mixture was filtered through Celite, concentrated andchromatographed (silica, CH₂Cl₂—MeOH) to give the title compounds as amixture of cis/trans isomers (3 mg). ESIMS m/z=813.61 [M+H]⁺.

Example 1-d

Step 1f. A mixture of 2,4′-dibromoacetophenone (5.00 g, 18.0 mmol) andN-Boc-L-proline (3.87 g, 18.0 mmol) in CH₃CN (60 mL) was added TEA (5.40mL, 37.8 mmol) slowly. The mixture was stirred at rt until thedisappearance of the starting material. The volatiles were evaporatedand the residue was partitioned (EtOAc—water). The organics were washedwith brine, dried (Na₂SO₄), filtered and evaporated. The residue waspurified by flash column chromatography (silica, hexanes-ethyl acetate)to give the desired compound as a light yellow foam (6.73 g, 91%). ¹HNMR (CDCl₃) 7.76 (t, J=8.0 Hz, 2H), 7.63 (dd, J=5.0, 8.5 Hz, 2H), 5.51,5.16 (2d, J=16.0 Hz, 1H), 5.32, 5.28 (2d, J=16.5 Hz, 1H), 4.48, 4.40(dd, J=5.0, 8.5 Hz, 1H), 3.56 (m, 1H), 3.43 (m, 1H), 2.30 (m, 2H), 2.06(m, 1H), 1.92 (m, 1H), 1.46, 1.43 (2s, 9H).

Step 1g. A solution of the compound from step if (6.73 g, 16.3 mmol) intoluene (100 mL) was added ammonium acetate (25.1 g, 0.327 mol) and theresultant mixture was heated up at 100° C. for 14 hours. The volatileswere evaporated and the residue was partitioned (EtOAc—aq. NaHCO₃). Theorganics were washed with brine, dried (Na₂SO₄), filtered andevaporated. The residue was purified by flash column chromatography(silica, hexanes-ethyl acetate) to give the desired compound as a yellowfoam (6.10 g, 95%). ESIMS m/z=392.24, 394.24 [M+H]⁺. ¹H NMR (CDCl₃) 7.57(bs, 1H), 7.48 (m, 3H), 7.23 (s, 1H), 4.97 (m, 1H), 3.42 (m, 2H), 2.99(m, 1H), 2.16 (m, 2H), 1.97 (m, 1H), 1.46 (s, 9H).

Step 1h. A mixture of(S)-2-(5-Bromo-1H-imidazol-2-yl)-pyrrolidine-1-carboxylic acidtert-butyl ester (prepared according to WO 2008/021927, 400.0 mg, 1.265mmol), trimethylsilylacetylene (1.79 ml, 12.65 mmol), CuI (3 mol %,0.03795 mmol) and Pd(PPh₃)₄ (10 mol %, 0.146 g, 0.1265 mmol) in THF (7mL) and Et₂N (3.53 mL, 25.30 mmol)) was degassed and then refluxed underN₂ for 24 hours before being allowed to cool down and concentrated. Theresidue was purified by flash column chromatography (silica,hexanes-ethyl acetate) to give the desired compound as a yellow foam(0.288 g, mixed with starting material). ESIMS m/z=649.41 [M+H]⁺.

Step 1i. A suspension of the compound from step 1h (0.288 g, theo.0.8636 mmol) and K₂CO₃ (0.298 g, 2.159 mmol) in methanol (10 ml) wasstirred at rt for 1 hour. The volatiles were evaporated off. The residuewas taken up in CH₂Cl₂/EtOAc (1/2) and filtered through a short pad ofsilica gel. The filtrate was concentrated. The residue was combined withanother bath (80 mg) and purified by flash column chromatography(silica, dichloromethane-ethyl acetate) to give the desired compound asa white solid (0.123 g, 31% over 2 steps). ESIMS m/z=262.17 [M+H]⁺.

Step 1j. A mixture of compound from step 1g (90.0 mg, 0.2296 mmol) andcompound from step 1i (60.0 mg, 0.2296 mmol), CuI (3 mol %, 0.00689mmol) and Pd(PPh₃)₄ (10 mol %, 26.5 mg, 0.02296 mmol) in acetonitrile (2mL) and Et₂N (0.3 mL) was degassed and then refluxed under N₂ for 16hours before being allowed to cool down and concentrated. The residuewas purified by flash column chromatography (silica, hexanes-ethylacetate) to give the desired compound as a yellow solid (56.9 mg 43%).ESIMS m/z=573.33 [M+H]⁺.

Example 299

Step 299a. A solution of the compound from step 1-d (56.9 mg, 0.0994mmol) in 1,4-dioxane (1.5 mL) was treated with HCl in 1,4-dioxane (4 M,6 mL) at rt for 30 minutes. The volatiles were evaporated off to givethe crude desired compound as a yellow solid which was used directly inthe next step.

Step 299b. A mixture of the crude compound from step 299a (0.0994 mmolat most) and (R)-(methoxycarbonyl)amino phenyl acetic acid (preparedaccording to WO 2008/021927, 52.0 mg, 0.248 mmol) in DMF (2.0 mL) wastreated with HATU (86.9 mg, 0.228 mmol) in the presence of DIPEA (0.35mL, 1.987 mmol) for 1.5 hours at rt and the volatiles were evaporatedoff to provide a brown syrup. The crude was purified by flash columnchromatography (silica, CH₂Cl₂—MeOH) to give the title compound as ayellow solid (75.0 mg, 100% over 2 steps). ESIMS m/z=755.37 [M+H]⁺.

Example 361

Step 361a. Pd(OH)₂ (20% on carbon, 17.0 mg) was added into a solution ofthe compound of example 299 (17.0 mg, 0.0225 mmol) in EtOH (2.0 mL). Thesuspension was purged with H₂ 3 time and stirred at rt for 4 h with a H₂balloon before being filtered through a short pad of Celite. Thefiltrate was concentrated. The crude was purified by flash columnchromatography (silica, CH₂Cl₂—MeOH) to give the title compound as awhite solid (10.1 mg, 59%). ESIMS m/z=759.36 [M+H]⁺.

Example 362

Step 362a. To a solution of(S)-2-(5-Bromo-1H-imidazol-2-yl)-pyrrolidine-1-carboxylic acidtent-butyl ester (prepared according to WO 2008/021927, 0.598 g, 1.892mmol) and di-tert-butyl dicarbonate (0.619 g, 2.838 mmol) indichloromethane (10 mL) and Et₃N (0.79 mL, 5.674 mmol)) was added DMAP(46.2 mg, 0.378 mmol) at rt. The solution was stirred at rt for 2 hoursbefore being concentrated. The residue was purified by flash columnchromatography (silica, hexanes-ethyl acetate) to give the desiredcompound as a white solid (0.758 g, 96%). ESIMS m/z=416.00, 418.00[M+H]⁺.

Step 362b. A mixture of the compound from step 362a (0.704 g, 1.691mmol), tributyl-(vinyl)tin (0.59 ml, 2.029 mmol) and Pd(PPh₃)₄ (5 mol %,97.7 mg, 0.0846 mmol) in toluene (8 mL) and Et₂N (3.53 mL, 25.30 mmol))was degassed and then refluxed under N₂ overnight before being allowedto cool down. It was directly purified by flash column chromatography(silica, hexanes-ethyl acetate) to give the desired compound as a whitesolid (0.450 g, 73%). ESIMS m/z=364.06 [M+H]⁺.

Step 362c. To a solution of the compound from step 362b (92.0 mg, 0.253mmol) in THF/H₂O (3/1, 4 ml) was added OsO₄ (4 wt % in H₂O, 0.03 mL, 2mol %), followed by NaIO4 (113.7 mg, 0.532 mmol) at rt. After 3 hours atrt, more NaIO4 (162.4 mg, 0.759 mmol) was added. After another 2 hoursat rt, the reaction was quenched with saturated Na₂S₂O₃ solution andextracted with EtOAc. The organics were washed with brine, dried(Na₂SO₄), filtered and concentrated. The crude product was used directlyfor next step.

Step 362d. A solution of the compound from step 362c (0.253 mmol atmost) in i-PrOH (4 mL) was treated with excess NaBH₄ at 0° C. until TLCindicated the completion of the reaction. Saturated NH₄Cl solution wascarefully added to quench the reaction. i-PrOH was evaporated off. Theresidue was extracted with EtOAc and dichloromethane. The organic layerwas washed with brine, dried (Na₂SO₄), filtered and concentrated. Thecrude product was combined with that from another batch (from 0.250 g ofthe compound from step 362b) and purified by flash column chromatography(silica, hexanes-ethyl acetate) to give the desired compound as a whitefoam (0.120 g, 35% over 2 steps). ESIMS m/z=368.08 [M+H]⁺.

Step 362e. A mixture of the compound from step 362d (0.120 g, 0.327mmol), (E)-but-2-ene-1,4-diyl tent-butyl dicarbonate (47.1 mg, 0.163mmol), Pd₂(dba)₃ (37.4 mg, 0.0408 mmol) and dppb (34.8 mg, 0.0816 mmol)in THF (3 mL) was degassed at rt and then refluxed under N₂ for 3.5hours before being allowed to cool down and concentrated. The residuewas purified by flash column chromatography (silica, hexanes-ethylacetate) to recover starting material (70.0 mg) and give the desiredcompound as a white foam (15.0 mg, 12%). ESIMS m/z=787.33 [M+H]⁺.

Step 362f. A solution of the compound from step 362e (15.0 mg, 0.0191mmol) in 1,4-dioxane (0.5 mL) was treated with HCl in 1,4-dioxane (4 M,2 mL) at rt for 1 h. The volatiles were evaporated off to give the crudedesired compound as a yellow solid which was used directly in the nextstep.

Step 362g. A mixture of the crude compound from step 362f (0.0191 mmolat most) and (S)-2-(methoxycarbonylamino)-3-methylbutanoic acid(prepared according to WO 2008/021927, 7.0 mg, 0.0400 mmol) in DMF (1.0mL) was treated with HATU (15.2 mg, 0.0400 mmol) in the presence ofDIPEA (0.066 mL, 0.381 mmol) for 2 hours at rt and the volatiles wereevaporated off to provide a brown syrup. The crude product was purifiedby flash column chromatography (silica, CH₂Cl₂-MeOH) to give the titlecompound as a white solid (6.8 mg, 51%). ESIMS m/z=701.17 [M+H]⁺.

Example 363

Step 363a. A mixture of the compound from step 362a (0.650 g, 1.56mmol), ethynyltrimethylsilane (2.16 mL, 15.6 mmol), CuI (8.9 mg, 46.8μmol) and Pd(PPh₃)₄ (90.3 mg, 78.1 mmol) in CH₃CN (5 mL) andtriethylamine (10 mL) was degassed and heated to 80° C. under N₂overnight. The volatiles were evaporated and the residue was partitioned(EtOAc—water). The organics were washed with brine, dried (Na₂SO₄),filtered and evaporated. The residue was purified by flash columnchromatography (silica, hexanes-ethyl acetate) to give the desiredcompound as a light yellow oil (0.560 g, 83%). ESIMS m/z=434.22 [M+H]⁺.

Step 363b. The compound from step 363a (0.560 g, 1.29 mmol) in MeOH (30mL) was treated with potassium carbonate (0.535 g, 3.88 mmol) for 30minutes before being evaporated to dryness. The residue was partitioned(EtOAc—water), and the organics were washed with brine, dried (Na₂SO₄),filtered and evaporated. The residue was purified by flash columnchromatography (silica, hexanes-ethyl acetate) to give the desiredcompound as a light yellow solid (0.312 g, 92%). ESIMS m/z=262.15[M+H]⁺.

Step 363c. A mixture of the compound from step 363b (0.103 g, 0.395mmol), 1,4-diiodo-benzene (62.0 mg, 0.188 mmol), CuI (2.1 mg, 11.2 μmol)and Pd(PPh₃)₄ (21.6 mg, 18.7 mmol) in CH₃CN (1 mL) and triethylamine (4mL) was degassed and heated to 60° C. under N₂ for 4 hours. Thevolatiles were evaporated and the residue was partitioned (EtOAc—water).The organics were washed with brine, dried (Na₂SO₄), filtered andevaporated. The residue was purified by flash column chromatography(silica, hexanes-ethyl acetate) to give the title compound as a verylight yellow solid (73.3 mg, 65%). ESIMS m/z=597.31 [M+H]⁺.

Example 364

Step 364a. A solution of the compound from Example 363 (73.3 mg, 0.123mmol) in 1,4-dioxane (1 mL) was treated with HCl in 1,4-dioxane (4 M, 4mL) rt for 30 minutes. The volatiles were evaporated off to give thecrude desired compound as a yellow solid which was directly used in thenext step. ESIMS m/z=397.26 [M+H]⁺.

Step 364b. A mixture of the crude compound from step 364a (0.123 mmol atmost) and (S)-2-(methoxycarbonylamino)-3-methylbutanoic acid (preparedaccording to WO 2008/021927, 45.2 mg, 0.258 mmol) in DMF (3 mL) wastreated with HATU (93.4 mg, 0.246 mmol) in the presence of DIPEA (0.31mL, 2.46 mmol) for 2 hours at rt and the volatiles were evaporated offto provide a brown sirup. It was purified by flash column chromatography(silica, CH₂Cl₂—MeOH) to give the title compound as a light yellow solid(62.1 mg, 2 steps 71%). ESIMS m/z=711.49 [M+H]⁺.

Example 365

A mixture of the compound of example 364 (23.0 mg, 32.3 μmol) andPd(OH)₂ on carbon (20% wt., 32.0 mg) in ethanol (3 mL) was treated withH₂ balloon overnight. The mixture was filtered through celite and thefiltrate was concentrated. The residue was purified by flash columnchromatography (silica, CH₂Cl₂—MeOH) to give the title compound as awhite solid (20.6 mg, 90%). ESIMS m/z=719.37 [M+H]⁺.

Example 366

A mixture of the compound from step 363b (0.150 g, 0.575 mmol),2,6-dibromonaphthalene (98.6 mg, 0.345 mmol), CuI (3.3 mg, 17.2 μmol)and Pd(PPh₃)₄ (33.2 mg, 28.7 μmol) in CH₃CN (1 mL) and triethylamine (4mL) was degassed and heated to 90° C. under N₂ overnight. The volatileswere evaporated and the residue was partitioned (EtOAc—water). Theorganics were washed with brine, dried (Na₂SO₄), filtered andevaporated. The residue was purified by flash column chromatography(silica, hexanes-ethyl acetate) to give the title compound as a verylight yellow solid (111 mg, 60%). ESIMS m/z=647.18 [M+H]⁺.

Example 367

The title compound was synthesized from the compound of Example 366using procedures similar to that described in Example 364. ESIMSm/z=761.35 [M+H]⁺.

Example 368

The title compound was synthesized from the compound of Example 367using procedures similar to that described in Example 365. ESIMSm/z=769.24 [M+H]⁺.

The remaining compounds of examples 1-360 may be prepared usingprocedures similar to that described in steps 1a-1j, 299, 361-368,and/or as described in the Synthetic Method.

TABLE 1 Examples 1-219

Entry

Entry

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

32

33

34

35

36

37

38

39

40

41

42

43

44

45

46

47

48

49

50

51

52

53

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55

56

57

58

59

60

61

62

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64

65

66

67

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84

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86

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94

95

96

97

98

99

100

101

102

103

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107

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112

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122

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128

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TABLE 2 Examples 220-229

Entry R R′ R″ X Entry R R′ R″ X 220 Me H H CH₂ 221 H H H CF₂ 222 Me H HS 223 H H H

224 Me H H O 225 H H H

226 H Ph H CH₂ 227 H H H

228 H H Ph CH₂ 229 H H H

TABLE 3 Examples 234-243

Entry R R′ R″ Entry R R′ R″ 234 Me Me H 235 H R′ H 236 Me H Me 237cyclopropyl Me H 238 Me Me Me 239 Me cyclopropyl H 240 Me Allyl H 241 EtMe H 242 Me CHMe₂ H 243 Me Et  H.

TABLE 4 Examples 244-263

Entry R R′ 244

245

246

247

248

249

250

251

252

253

254

255

256

257

258

259

260

261

262

263

TABLE 5 Examples 264-283

Entry R R′ R″ R′′′ Entry R R′ R″ R′′′ 264 F H H H 265 F H F H 266 F F HH 267 Me H H H 268 Me Me H H 269 Me H Me H 270 CF₃ H H H 271 CF₃ H CF₃ H272 CF₃ CF₃ H H 273 CO₂Me H H H 274 CONH₂ H H H 275 CO₂H H H H 276 CH₂OHH H H 277 CH₂NMe₂ H H H 278 NMe₂ H H H 279 OMe H H H 280 OCF₃ H H H 281NHCO₂Me H H H 282 Cl H H H 283 Cl H Cl  H.

TABLE 6 Examples 284-360

Entry A^(a) Entry A^(a) 284

285

286

287

288

289

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297

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300

301

302

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321

322

323

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325

326

327

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329

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331

332

333

334

335

336

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339

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359

360

Biological Activity 1. HCV Replicon Cell Lines

HCV replicon cell lines (kindly provided by R. Bartenschlager) isolatedfrom colonies as described by Lohman et al. (Lohman et al. (1999)Science 285: 110-113, expressly incorporated by reference in itsentirety) and used for all experiments. The HCV replicon has the nucleicacid sequence set forth in EMBL Accession No.: AJ242651, the codingsequence of which is from nucleotides 1801 to 8406.

The coding sequence of the published HCV replicon was synthesized andsubsequently assembled in a modified plasmid pBR322 (Promega, Madison,Wis.) using standard molecular biology techniques. One replicon cellline (“SGR 11-7”) stably expresses HCV replicon RNA which consists of(i) the HCV 5′UTR fused to the first 12 amino acids of the capsidprotein, (ii) the neomycin phosphotransferase gene (neo), (iii) the IRESfrom encephalomyocarditis virus (EMCV), and (iv) HCV NS2 to NS5B genesand the HCV 3′UTR. Another replicon cell line (“Huh-luc/neo-ET”)described by Vrolijk et al. (Vrolijk et. al. (2003) Journal ofVirological Methods 110:201-209, expressly incorporated by reference inits entirety) stably expresses HCV replicon RNA which consists of (i)the HCV 5′UTR fused to the first 12 amino acids of the capsid protein,(ii) the firefly luciferase reporter gene, (iii) the ubiquitin gene,(iv) the neomycin phosphotransferase gene (neo), (v) the IRES fromencephalomyocarditis virus (EMCV), and (vi) HCV NS3 to NS5B genes thatharbor cell culture adaptive mutations (E1202G, T12801, K1846T) and theHCV 3′UTR.

These cell lines were maintained at 37° C., 5% CO₂, 100% relativehumidity in DMEM (Cat# 11965-084, Invitrogen), with 10% fetal calf serum(“FCS”, Invitrogen), 1% non-essential amino acids (Invitrogen), 1% ofGlutamax (Invitrogen), 1% of 100× penicillin/streptomycin (Cat#15140-122, Invitrogen) and Geneticin (Cat# 10131-027, Invitrogen) at0.75 mg/ml or 0.5 mg/ml for 11-7 and Huh-luc/neo-ET cells, respectively.

2. HCV Replicon Assay—qRT-PCR

EC₅₀ values of single agent compounds and combinations were determinedby HCV RNA detection using quantitative RT-PCR, according to themanufacturer's instructions, with a TaqMan® One-Step RT-PCR Master MixReagents Kit (Cat# AB 4309169, Applied Biosystems) on an ABI Model 7500thermocycler. The TaqMan primers used for detecting and quantifying HCVRNA were obtained from Integrated DNA Technologies. HCV RNA wasnormalized to GAPDH RNA levels in drug-treated cells, which is detectedand quantified using the Human GAPDH Endogenous Control Mix (AppliedBiosystems, AB 4310884E). Total cellular RNA is purified from 96-wellplates using the RNAqueous 96 kit (Ambion, Cat# AM1812). Chemical agentcytotoxicity is evaluated using an MTS assay according to themanufacturer's directions (Promega).

3. HCV Replicon Assay—Luciferase

Since clinical drug resistance often develops in viral infectionsfollowing single agent therapies, there is a need to assess theadditive, antagonistic, or synergistic properties of combinationtherapies. We used the HCV replicon system to assess the potential useof the compound of the present invention or in combination therapieswith Interferon alpha, cyclosporine analogs and inhibitors targetingother HCV proteins. The acute effects of a single or combinations ofdrugs are studied in the “Huh-luc/neo-ET” replicon with each chemicalagent titrated in an X or Y direction in a 6 point two-fold dilutioncurve centered around the EC50 of each drug. Briefly, replicon cells areseeded at 7,000 cells per well in 90 ul DMEM (without phenol red,Invitrogen Cat.# 31053-036) per well with 10% FCS, 1% non-essentialamino acids, 1% of Glutamax and 1% of 100× penicillin/streptomycin andincubated overnight at 37° C., 5% CO₂, 100% relative humidity. 16-20 hafter seeding cells, test compounds previously solubilized and titratedin dimethyl sulfoxide (“DMSO”) from each X plate and Y plate are diluted1:100 in DMEM (without phenol red, Invitrogen Cat.# 31053-036) with 10%FCS, 1% non-essential amino acids, 1% of Glutamax and 1% of 100×penicillin/streptomycin and added directly to the 96-well platecontaining cells and growth medium at a 1:10 dilution for a finaldilution of compound and DMSO of 1:1000 (0.2% DMSO final concentration).Drug treated cells are incubated at 37° C., 5% CO₂, 100% relativehumidity for 72 hours before performing a luciferase assay using 100 ulper well BriteLite Plus (Perkin Elmer) according to the manufacturer'sinstructions. Data analysis utilizes the method published by Prichardand Shipman (Antiviral Research, 1990. 14:181-205). Using this method,the combination data are analyzed for antagonistic, additive, orsynergistic combination effects across the entire combination surfacecreated by the diluted compounds in combination.

The compounds of the present invention may inhibit HCV by mechanisms inaddition to or other than NS5A inhibition. In one embodiment thecompounds of the present invention inhibit HCV replicon and in anotherembodiment the compounds of the present invention inhibit NS5A.

The compounds of the present invention can be effective against the HCV1b genotype. It should also be understood that the compounds of thepresent invention can inhibit multiple genotypes of HCV. In oneembodiment compound of the present invention are active against the 1a,1b, 2a, 2b, 3a, 4a, and 5a genotypes. Table 9 shows the EC₅₀ values ofrepresentative compounds of the present invention against the HCV 1bgenotype from the above described qRT-PCR or luciferase assay. EC₅₀ranges against HCV 1b are as follows: A >10 nM; B 1-10 nM; C <1 nM.

TABLE 9 Genotype-1b replicon EC₅₀ Example Range Example Range ExampleRange 1-b C 1-c C 299 C 361 C 362 A 364 C 365 B 367 C 368 B

1. A compound represented by Formula (I)

or a pharmaceutically acceptable salt thereof, wherein: A is absent or acyclic group independently selected from aryl, heteroaryl, heterocyclic,C₃-C₈ cycloalkyl, and C₃-C₈ cycloalkenyl, each optionally substituted; Yis absent or an optionally substituted aliphatic group selected from thegroup consisting of O, S, N(R¹¹), C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈alkynyl, C₃-C₈ cycloalkyl, C₃-C₈ cycloalkenyl, and heterocyclic, eachoptionally substituted; or a combination thereof; Z is absent or anoptionally substituted linear aliphatic group; Wherein at least two ofA, Y, and Z are present; R¹¹ at each occurrence is independentlyhydrogen or optionally substituted C₁-C₈ alkyl; R¹ and R² at eachoccurrence are each independently selected from the group consisting ofhydrogen, halogen, cyano, optionally substituted C₁-C₄ alkyl, —O—R¹¹,—NR^(a)R^(b), —C(O)R¹¹, —CO₂R¹¹, and —C(O)NR^(a)R^(b); R^(a) and R^(b)at each occurrence are each independently selected from the groupconsisting of hydrogen, optionally substituted C₁-C₈ alkyl, andoptionally substituted C₂-C₈ alkenyl; or R^(a) and R^(b) can be takentogether with the nitrogen atom to which they are attached to form anoptionally substituted heterocyclic or optionally substituted heteroarylgroup; Q and J are each independently selected from:

R³ and R⁴ at each occurrence are each independently selected from thegroup consisting of hydrogen, optionally substituted C₁-C₈ alkyl,optionally substituted C₂-C₈ alkenyl, and optionally substituted C₃-C₈cycloalkyl; or alternatively, R³ and R⁴ can be taken together with thecarbon atom to which they are attached to form optionally substitutedC₃-C₈ cycloalkyl or optionally substituted heterocyclic; R⁵ at eachoccurrence is independently hydrogen, optionally substituted C₁-C₈alkyl, or optionally substituted C₃-C₈ cycloalkyl; R⁶ is selected fromthe group consisting of —C(O)—R¹², —C(O)—C(O)—R¹², —S(O)₂—R¹², and—C(S)—R¹²; R¹² at each occurrence is independently selected from thegroup consisting of: —O—R¹¹, —NR^(a)R^(b), —R¹³, and —NR^(c)R^(d); R¹³at each occurrence is independently selected from the group consistingof: hydrogen, C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, C₃-C₈cycloalkyl, C₃-C₈ cycloalkenyl, heterocyclic, aryl, and heteroaryl, eachoptionally substituted; R^(c) and R^(d) at each occurrence are eachindependently selected from the group consisting of hydrogen, —R¹³,—C(O)—R¹³, —C(O)—OR¹³, —S(O)₂—R¹³, —C(O)N(R¹³)₂, and —S(O)₂N(R¹³)₂; m is0, 1, or 2; n is 1, 2, 3, or 4; X is selected from O, S, S(O), SO₂, andC(R⁷)₂; provided that when m is 0, X is C(R⁷)₂; and R⁷ at eachoccurrence is independently selected from the group consisting of:hydrogen, halogen, cyano, —O—R¹¹, —NR^(a)R^(b), optionally substitutedaryl, optionally substituted heteroaryl, and optionally substituted—C₁-C₄ alkyl; or two vicinal R⁷ groups can be taken together with thetwo adjacent atoms to which they are attached to form a fused,optionally substituted C₃-C₈ cycloalkyl or optionally substitutedheterocyclic ring; or alternatively two geminal R⁷ groups can be takentogether with the carbon atom to which they are attached to form aspiro, optionally substituted C₃-C₈ cycloalkyl or optionally substitutedheterocyclic ring.
 2. The compound of claim 1, wherein Z is a linearaliphatic group that contains a group selected from O, N(R¹¹), C(O),S(O)₂, C(O)O, C(O)N(R¹¹), OC(O)O, OC(O)N(R¹¹), S(O)₂N(R¹¹),N(R¹¹)C(O)N(R¹¹), N(R¹¹)C(O)C(O)N(R¹¹), N(R¹¹)S(O)₂N(R¹¹),C(O)N(R¹¹)S(O)₂ and C(O)N(R¹¹)S(O)₂N(R¹¹).
 3. The compound of claim 1,wherein Q and J are each independently selected from:

wherein X is independently CH₂, CF₂, CHF, or CH(OH); or apharmaceutically acceptable salt thereof.
 4. The compound of claim 1,wherein Q and J are each independently

and R¹ and R² are each independently hydrogen; or a pharmaceuticallyacceptable salt thereof.
 5. The compound of claim 1, wherein A is absentand each of Y and Z are present; or a pharmaceutically acceptable saltthereof.
 6. The compound of claim 1, wherein Y is absent and each of Aand Z are present; or a pharmaceutically acceptable salt thereof.
 7. Thecompound of claim 1, wherein Z is absent and each of A and Y arepresent; or a pharmaceutically acceptable salt thereof.
 8. The compoundof claim 1, wherein each of A, Y and Z are present; or apharmaceutically acceptable salt thereof.
 9. The compound of claim 5,wherein Z is C₁-C₈ alkyl, C₂-C₈ alkenyl, or C₂-C₈ alkynyl, eachoptionally substituted, or Z is a group containing between one and eightcarbon atoms and optionally contains one group selected from O, N(R¹¹),C(O), S(O)₂, C(O)O, C(O)N(R¹¹), OC(O)O, OC(O)N(R¹¹), S(O)₂N(R¹¹),N(R¹¹)C(O)N(R¹¹), N(R¹¹)C(O)C(O)N(R¹¹), N(R¹¹)S(O)₂N(R¹¹),C(O)N(R¹¹)S(O)₂ and C(O)N(R¹¹)S(O)₂N(R¹¹); or a pharmaceuticallyacceptable salt thereof.
 10. The compound of claim 5, wherein Y isselected from optionally substituted C₃-C₈ cycloalkyl, optionallysubstituted C₃-C₈ cycloalkenyl, or optionally substituted heterocyclic;or a pharmaceutically acceptable salt thereof.
 11. The compound of claim7, wherein A is an optionally substituted aryl or optionally substitutedheteroaryl; or a pharmaceutically acceptable salt thereof.
 12. Thecompound of claim 7, wherein A is an optionally substituted aryl oroptionally substituted heteroaryl; and Y is selected from an optionallysubstituted heterocyclic, optionally substituted C₃-C₈ cycloalkyl oroptionally substituted C₃-C₈ cycloalkenyl; or a pharmaceuticallyacceptable salt thereof.
 13. The compound of claim 8, wherein Y and Zare each independently C₁-C₄ alkyl, C₂-C₄ alkenyl, or C₂-C₄ alkynyl,each optionally substituted, or wherein Y and Z are each independently alinear aliphatic group containing between one and four carbon atoms andoptionally containing one or more groups independently selected from Oand N(R¹¹); or a pharmaceutically acceptable salt thereof.
 14. Thecompound according to claim 1 selected from the group of compounds1-a˜1-d and 1-360 shown below:

Compounds 1-219

Entry

Entry

Entry

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

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209

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211

212

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215

216

217

218

219

Compounds 220-229

Entry R R′ R″ X Entry R R′ R″ X 220 Me H H CH₂ 221 H H H CF₂ 222 Me H HS 223 H H H

224 Me H H O 225 H H H

226 H Ph H CH₂ 227 H H H

228 H H Ph CH₂ 229 H H H

Compounds 234-243

Entry R R′ R″ Entry R R′ R″ 234 Me Me H 235 H Me H 236 Me H Me 237cyclopropyl Me H 238 Me Me Me 239 Me cyclopropyl H 240 Me Allyl H 241 EtMe H 242 Me CHMe₂ H 243 Me Et H

Compounds 244-263

Entry R R′ Entry R R′ 244

245

246

247

248

249

250

251

252

253

254

255

256

257

258

259

260

261

262

263

Compounds 264-283

Entry R R′ R″ R′′′ Entry R R′ R″ R′′′ 264 F H H H 265 F H F H 266 F F HH 267 Me H H H 268 Me Me H H 269 Me H Me H 270 CF₃ H H H 271 CF₃ H CF₃ H272 CF₃ CF₃ H H 273 CO₂Me H H H 274 CONH₂ H H H 275 CO₂H H H H 276 CH₂OHH H H 277 CH₂NMe₂ H H H 278 NMe₂ H H H 279 OMe H H H 280 OCF₃ H H H 281NHCO₂Me H H H 282 Cl H H H 283 Cl H Cl H

Compounds 284-360

Entry A^(a) Entry A^(a) 284

285

286

287

288

289

290

291

292

293

294

295

296

297

298

299

300

301

302

303

304

305

306

307

310

311

312

313

314

315

316

317

318

319

320

321

322

323

324

325

326

327

328

329

330

331

332

333

334

335

336

337

338

339

340

341

342

343

344

345

346

347

348

349

350

351

352

353

354

355

356

357

358

359

360


15. A pharmaceutical composition comprising a compound or a combinationof compounds according to claim 1 or a pharmaceutically acceptable saltthereof, in combination with a pharmaceutically acceptable carrier orexcipient.
 16. A method of inhibiting the replication of anRNA-containing virus comprising contacting said virus with atherapeutically effective amount of a compound or combination ofcompounds of claim 1, or a pharmaceutically acceptable salt thereof. 17.A method of treating or preventing infection caused by an RNA-containingvirus comprising administering to a patient in need of such treatment atherapeutically effective amount of a compound or combination ofcompounds of claim 1, or a pharmaceutically acceptable salt thereof. 18.The method of claim 17, wherein the RNA-containing virus is hepatitis Cvirus.
 19. The method of claim 17, further comprising the step ofco-administering one or more agents selected from the group consistingof a host immune modulator and an antiviral agent, or a combinationthereof.
 20. The method of claim 19, wherein the host immune modulatoris selected from the group consisting of interferon-alpha,pegylated-interferon-alpha, interferon-beta, interferon-gamma, consensusinterferon, a cytokine, and a vaccine.
 21. The method of claim 19wherein the antiviral agent inhibit replication of HCV by inhibitinghost cellular functions associated with viral replication.
 22. Themethod of claim 19 wherein the antiviral agent inhibit the replicationof HCV by targeting proteins of the viral genome.
 23. The method ofclaim 19, wherein said antiviral agent is an inhibitor of a HCV viralprotein, a replication process or a combination thereof, wherein saidtargeting protein or replication process is selected from the groupconsisting of helicase, protease, polymerase, metalloprotease, NS4A,NS4B, NS5A, assembly, entry, and IRES.
 24. The method of claim 17further comprising the step of co-administering an agent or combinationof agents that treat or alleviate symptoms of HCV infection selectedfrom cirrhosis and inflammation of the liver.
 25. The method of claim17, further comprising the step of co-administering one or more agentsthat treat patients for disease caused by hepatitis B (HBV) infection.26. The method of claim 17, further comprising the step ofco-administering one or more agents that treat patients for diseasecaused by human immunodeficiency virus (HIV) infection.
 27. A compoundof claim 1, wherein R¹ and R² are hydrogen; Q and J are eachindependently

wherein n is 1 or 2; X at each occurrence is independently CH₂, CF₂,CHF, or C(R⁷)₂; R¹² is C₁-C₈ alkyl optionally substituted with amino,hydroxy, phenyl, protected amino, or O(C₁-C₄ alkyl); R⁷ at eachoccurrence is each independently hydrogen, Me, fluoro or hydroxy; oroptionally, two vicinal R⁷ groups taken together with the two adjacentatoms to which they are attached form a fused, optionally substitutedC₃-C₈ cycloalkyl; or alternatively and optionally, two geminal R⁷ groupstaken together with the carbon atom to which they are attached form aspiro, optionally substituted C₃-C₈ cycloalkyl; or a pharmaceuticallyacceptable salt thereof.
 28. The compound of claim 27, wherein

is selected from the group listed below, or a pharmaceuticallyacceptable salt thereof:


29. A compound according to claim 1, selected from the group ofcompounds 361-368 compiled in the following table: 361

362

363

364

365

366

367

368


30. The pharmaceutical composition of claim 15, further comprising anagent selected from interferon, pegylated interferon, ribavirin,amantadine, an HCV protease inhibitor, an HCV polymerase inhibitor, anHCV helicase inhibitor, or an internal ribosome entry site inhibitor.31. The composition of claim 15, further comprising a cytochrome P450monooxygenase inhibitor or a pharmaceutically acceptable salt thereof.32. The composition of claim 31, wherein the cytochrome P450monooxygenase inhibitor is ritonavir.
 33. A method of treating hepatitisC viral infection in a subject in need thereof comprisingco-administering to said subject a cytochrome P450 monooxygenaseinhibitor or a pharmaceutically acceptable salt thereof, and a compoundof claim 1 or a pharmaceutically acceptable salt thereof.